tenosynovial giant cell tumours

tenosynovial giant

cell tumours

monique J.l. mastboom

Although it’s rare, it still needs care

PROEFSCHRIFT

ter verkrijging van

de graad van Doctor aan de Universiteit van Leiden,

op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker,

volgens besluit van het College voor Promoties

te verdedigen op dinsdag 13 november 2018

klokke 16.15 uur

door

Monique J.L. Mastboom

geboren op 19 oktober 1988

te Nijmegen, Nederland

tenosynovial giant cell

tumours

Cover design and thesis layout Lisanne de Koster

ISBN 978-94-9301-479-4

Printed by Gildeprint, Enschede, the Netherlands

Copyright © 2018 by Monique Mastboom

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means

without permission in writing from the author. The copyright of the articles has been transferred to the

respective journals.

The conduction of the research included in this thesis was carried out at the Department of Orthopaedics of

the Leiden University Medical Centre, Leiden, the Netherlands.

The printing of this thesis was financially supported by Universiteit Leiden, Daiichi Sankyo, Implantcast

Benelux, Anna-Fonds, ChipSoft, MoElBaDa, Consul-TENT, Bedrijfestijn. All funding is gratefully acknowledged.

Promotores

Prof. dr. P.D.S. Dijkstra

Prof. dr. A.J. Gelderblom

Co-promotor

Dr. M.A.J. van de Sande

Leden promotiecommissie

Prof. dr. J.V.M.G. Bovee

Prof. dr. W.T.A. van der Graaf The Royal Marsden NHS Foundation Trust, London

Dr. I.C.M. van der Geest Radboud Universitair Medisch Centrum, Nijmegen

General introduction and outline of this thesis

Incidence

Higher incidence rates than previously known in Tenosynovial Giant Cell Tumours

M.J.L. Mastboom, F.G.M. Verspoor, A.J. Verschoor, D. Uittenbogaard, B. Nemeth, W.J.B.

Mastboom, J.V.M.G. Bovee, P.D.S. Dijkstra, H.W.B. Schreuder, H. Gelderblom, M.A.J. van

de Sande, TGCT study group.

Acta Orthop. 2017 Dec;88(6):688-694

Diagnostics

Does CSF1 over-expression or rearrangement influence biological behaviour

in Tenosynovial Giant Cell Tumours of the knee?

M.J.L. Mastboom, D.M. Hoek, J.V.M.G. Bovee, M.A.J. van de Sande*, K. Szuhai* (*Shared

last authorship).

Histopathology 2018 Aug. doi: 10.1111/his.13744

Disease severity

Severity classification of Tenosynovial Giant Cell Tumours on MR imaging

M.J.L. Mastboom*, F.G.M. Verspoor*, D.F. Hanff, M.G.J. Gademan, P.D.S. Dijkstra, H.W.B.

Schreuder, J.L. Bloem, R.J.P. van der Wal, M.A.J. van de Sande (*Shared first authorship).

Surg Oncol. 2018 Sept;27(3):544-550

Hormones

Can increased symptoms of Tenosynovial Giant Cell Tumours during

pregnancy be explained by a change in female sex hormones?

M.J.L. Mastboom, F.G.M. Verspoor, R. Planje, H.W.B. Schreuder, M.A.J. van de Sande.

Submitted

table of contents

11

28

48

70

94

Chapter 1.

Chapter 2.

Chapter 3.

Chapter 4.

Chapter 5.

114

134

162

190

Chapter 6.

Chapter 7.

Chapter 8.

Chapter 9.

Children

Tenosynovial Giant Cell Tumours in children: a similar entity compared with adults

M.J.L. Mastboom, F.G.M. Verspoor, D. Uittenbogaard, G.R. Schaap, P.C. Jutte, H.W.B.

Schreuder, M.A.J. van de Sande.

Clin Orthop Relat Res. 2018 Sept;476(9):1803-1812

Localized-TGCT

Surgical treatment of localized-type Tenosynovial Giant Cell tumours of large joints

M.J.L. Mastboom, E. Staals, F.G.M. Verspoor, A.J. Rueten-Budde, S. Stacchiotti, E.

Palmerini, G.R. Schaap, P.C. Jutte, W. Aston, A. Leithner, D. Dammerer, A. Takeuchi, Q.

Thio, X. Niu, J.S. Wunder, TGCT study group, M.A.J. van de Sande.

Submitted

Diffuse-TGCT

Outcome of surgical treatment for patients with diffuse-type Tenosynovial

Giant Cell Tumours

M.J.L. Mastboom, E. Palmerini, F.G.M. Verspoor, A.J. Rueten-Budde, S. Stacchiotti, E.

Staals, G.R. Schaap, P.C. Jutte, W. Aston, H. Gelderblom, A. Leithner, D. Dammerer, A.

Takeuchi, Q. Thio, X. Niu, J.S. Wunder, TGCT study group, M.A.J. van de Sande.

Submitted

Treatment

Long-term efficacy of imatinib mesylate in patients with advanced

Tenosynovial Giant Cell Tumour

M.J.L. Mastboom*, F.G.M. Verspoor*, G. Hannink, R.G. Maki, A. Wagner, E. Bompas, J. Desai,

A. Italiano, B.M. Seddon, W.T.A. van der Graaf, J.Y. Blay, M. Brahmi, L. Eberst, S. Stacchiotti,

O. Mir, M.A.J. van de Sande, H. Gelderblom, P.A. Cassier (*Shared first authorship).

Submitted

Quality of life

The effect of surgery in Tenosynovial Giant Cell Tumours as measured by

patient reported outcomes on quality of life and joint function

M.J.L. Mastboom*, F.G.M. Verspoor*, G. Hannink, W.T.A. van der Graaf, M.A.J. van de

Sande, H.W.B. Schreuder (*Shared first authorship).

Accepted in Bone Joint J

Impact on daily living

The patient perspective on the impact of Tenosynovial Giant Cell Tumours

on daily living: Crowdsourcing study on physical function and quality of life

M.J.L. Mastboom, R. Planje, M.A.J. van de Sande.

Interact J Med Res. 2018 Feb 23;7(1):e4.

Limb amputation

Limb amputation after multiple treatments of Tenosynovial Giant Cell

Tumour: Series of 4 Dutch cases

M.J.L. Mastboom, F.G.M. Verspoor, H. Gelderblom, M.A.J. van de Sande.

Case Rep Orthop. 2017;7402570.

Summary of this thesis

General discussion & Future perspectives

Summary in Dutch (Nederlandse samenvatting)

Appendices

List of publications

Acknowledgements

Curriculum vitae

208

232

258

274

284

304

316

Chapter 10.

Chapter 11.

Chapter 12.

Chapter 13.

Chapter 14.

Chapter 15.

Chapter 16.

general introduction

and outlineof this thesis intr

oduc

tionch

apte

r on

e

14

Chapter one

Background

Tenosynovial Giant Cell Tumour (TGCT) is an orphan, mono-articular disease, arising from

the synovial lining of joints, bursae or tendon sheaths1, 2. TGCT is divided into a lobulated

well circumscribed lesion (localized-type) and a more locally aggressive lesion (diffuse-type)

(figure 1). In general, the disease is considered a benign entity, but the diffuse-type can invade

surrounding tissues and is regarded as locally invasive1, 2. The best treatment modality for this

disease is a highly discussed topic. Literature about this disease is scarce. However, the impact

of the disease can be severe: a deteriorated joint function threatens the quality of life in the

relatively young patient population3-5. Therefore, it is of upmost importance to gain insight in

the pathophysiology and severity of the disease to improve treatment strategies.

Historical vignette

In the 2013 WHO classification, giant cell tumour of the tendon sheath and pigmented villonodular

synovitis (PVNS) were unified in one overarching name: tenosynovial giant cell tumours (TGCT)

(table 1)1, 2. Historically, different terms have been used for this entity, including synovial

xanthoma, xanthogranuloma, synovial fibroendothelioma or endothelioma, xanthomatous

giant cell tumour of the tendon sheath, myeloplaxoma, chronic haemorrhagic villous synovitis,

giant cell fibrohaemangioma, fibrohaemosideric sarcoma, sarcoma fusigiganocellulare, benign

or malignant polymorphocellular tumour of the synovial membrane, and fibrous xanthoma of

the synovial membrane6-9.

In 1852, Chassaignac reported a nodular lesion of the synovial membrane affecting the flexor

tendons of the fingers10. Simon was the first to describe the localized form11 and Moser the

first to define the diffuse form affecting the knee12. At that time, the disorder was considered a

malignant condition. Dowd was the first person to question this13. Jaffe elucidated the clinical,

radiological and pathological characteristics of the yellow-brown tumor-like tenosynovial

lesions and suggested a reactive or inflammatory origin of the disease as both nodular

synovitis and pigmented villonodular synovitis (PVNS) showed similar histological features

and both showed a benign course6. The authors also merged both localized- and diffuse-forms

to PVNS. However, the condition was considered neoplastic after the discovery of numerical


15

1

Figure 1 A 65-year-old female patient with a large medical history, consisting of multiple mutilating

diffuse-type TGCT-related surgeries of her right knee. a. Swollen right knee in bonnet position. On the

posterior, medial side is TGCT growing outside the operation-scar (arrow-head). b. Sagittal Short-TI

Inversion Recovery metal clear MR image, revealing extensive tumour growth, also extending superficially

into the skin (arrow-head). Characteristic TGCT blooming effect is seen attributed to scattered areas of low

signal intensity, typical for iron deposition. c. Positron emission tomography–computed tomography (PET-

CT): enhancement around total knee replacement, suspect for recurrent TGCT. d. Macroscopic aspect of

this tumour after surgical removal, including the typical red-brownish colours and villous appearance. This

section shows the extensive TGCT with a polypus bulge growing into the skin (arrow-head).

a b

dc

16

Chapter one

and structural chromosomal aberrations14-20. At present, an inflammatory disease component

remains, as only a small part of TGCT encompassing cells are considered neoplastic or tumour

cells (2-16%). These neoplastic cells express elevated levels of CSF1, resulting in an increase of

neoplastic cells by an autocrine-loop as well as the recruitment of multiple non-neoplastic cells

by a paracrine Ioop. This phenomenon is coined as ‘the landscape effect’21, 22.

aetiology

Chromosomal aberrations, in both localized- and

diffuse-TGCT, include trisomy for chromosomes 5

and 7 and translocations involving 1p11-13, most

commonly partnering with 2q37 emerging in a

t(1;2)(p13,q37) translocation (figure 2). At the 1p13

breakpoint, the Colony Stimulating Factor 1 (CSF1)

gene is located. In both TGCT subtypes, CSF1 is

fused to the collagen 6A3 (COL6A3) promotor. As

a result, the fusion leads to deregulated expression

of CSF121 (figure 3).

1 #

#

2

Figure 2 Systemic partial karyotype showing

characteristic TGCT translocation t(1;2)(p13;q37).

Source: CyDAS Online Analysis Site,

http://www.cydas.org/OnlineAnalysis/


17

1Figure 3 Etiopathogenesis of

TGCT, neoplastic cells carrying

the translocation (t(1;2)

(p13;q37)), express elevated

levels of CSF1 (red triangles).

This results in an increase of

neoplastic cells through an

autocrine loop. In addition, the

recruitment of inflammatory cells

of the monocyte/macrophage

lineage expressing the CSF1

receptor (paracrine loop), results

in the tumour-landscape effect.

Source: permission obtained from

designer drs. D.M. Hoek

18

Chapter one

Table 1 Chronological literature overview on acquaintance of Tenosynovial Giant Cell Tumours

Study Jaffe (1941)6 Fletcher (1992)14 Cin (1994)15 West (2006)21 Cupp (2007)22 WHO (2013)1, 2 Panagopoulos (2014)56

Name Pigmented Villonodular Synovititis (PVNS)

Tenosynovial Giant Cell Tumour (TGCT)

Types Circumscribed formaffected membrane ≥1 yellow-

brown sessile/stalked tumor-like nodular outgrowths

Diffuse form brownishly pigmented

membrane, covered by villous and coarse nodular outgrowths

Localized-typewell circumscribed, small (0.5-4 cm) and lobulated

tumour

Diffuse-typeLarge (>5 cm) firm or sponge-like tumour,

typical villous pattern and multi-nodular appearance

with variegated colours

Definition Mono-articular, regarded synovium of tendon sheath,

bursa, and joint.

Histopathological features

Multinuclear giant cells, hemosiderinladen

macrophages and lipophages,alternate with areas of

intercellular collagen and hyalin

Mononuclear and multinucleated cells, both showing high

levels of CSF1R

Perinuclear CSF1 protein expression within

mononuclear cells in a diffuse, punctate pattern

Synovial like mononuclear cells, multinucleated

osteoclast-like giant cells, foam cells, siderophages,

inflammatory cells

Tumourigenesis Inflammatory response, unknown to what agent

Numerical changes (trisomy) in

chromosome 5 and 7

Structural aberrations (short arm) 1p11-13

Neoplastic (CSF1 rearrangement, including strong promotor region

COL6A3 gene) and non-neoplastic

Central mechanism of tumorigenesis is

the signaling pathway initiated by CSF1 and

CSF1R interaction

Tumour characteristics

Different parts of individual lesions vary widely. A

considerable number of blood vessels and much blood

pigment

Landscape effect; a minority of

neoplastic cells (CSF1 overexpression) create

a tumour landscape comprised of non-

neoplastic cells

Two groups:1: both CSF1

translocation and high expression of CSF1 RNA

(61%).

2: no detectable translocation, but high expression of CSF1 RNA or CSF1 protein (39%)

Case-report: inversion t(1;1)(q21;p11), resulting

in CSF1-100A10 fusion gene, indicates replacement of 3’-UTR of CSF1 in abirritations

targeting CSF1 gene


19

1Table 1 Chronological literature overview on acquaintance of Tenosynovial Giant Cell Tumours

Study Jaffe (1941)6 Fletcher (1992)14 Cin (1994)15 West (2006)21 Cupp (2007)22 WHO (2013)1, 2 Panagopoulos (2014)56

Name Pigmented Villonodular Synovititis (PVNS)

Tenosynovial Giant Cell Tumour (TGCT)

Types Circumscribed formaffected membrane ≥1 yellow-

brown sessile/stalked tumor-like nodular outgrowths

Diffuse form brownishly pigmented

membrane, covered by villous and coarse nodular outgrowths

Localized-typewell circumscribed, small (0.5-4 cm) and lobulated

tumour

Diffuse-typeLarge (>5 cm) firm or sponge-like tumour,

typical villous pattern and multi-nodular appearance

with variegated colours

Definition Mono-articular, regarded synovium of tendon sheath,

bursa, and joint.

Histopathological features

Multinuclear giant cells, hemosiderinladen

macrophages and lipophages,alternate with areas of

intercellular collagen and hyalin

Mononuclear and multinucleated cells, both showing high

levels of CSF1R

Perinuclear CSF1 protein expression within

mononuclear cells in a diffuse, punctate pattern

Synovial like mononuclear cells, multinucleated

osteoclast-like giant cells, foam cells, siderophages,

inflammatory cells

Tumourigenesis Inflammatory response, unknown to what agent

Numerical changes (trisomy) in

chromosome 5 and 7

Structural aberrations (short arm) 1p11-13

Neoplastic (CSF1 rearrangement, including strong promotor region

COL6A3 gene) and non-neoplastic

Central mechanism of tumorigenesis is

the signaling pathway initiated by CSF1 and

CSF1R interaction

Tumour characteristics

Different parts of individual lesions vary widely. A

considerable number of blood vessels and much blood

pigment

Landscape effect; a minority of

neoplastic cells (CSF1 overexpression) create

a tumour landscape comprised of non-

neoplastic cells

Two groups:1: both CSF1

translocation and high expression of CSF1 RNA

(61%).

2: no detectable translocation, but high expression of CSF1 RNA or CSF1 protein (39%)

Case-report: inversion t(1;1)(q21;p11), resulting

in CSF1-100A10 fusion gene, indicates replacement of 3’-UTR of CSF1 in abirritations

targeting CSF1 gene

Empty fields remained unchanged.

CSF1: Colony Stimulating Factor 1; CSF1R: Colony Stimulating Factor 1 Receptor.

20

Chapter one

macroscopy and microscopy

Definite diagnosis of TGCT is established on microscopy.

Macroscopically, localized-TGCT is an encapsulated or pedunculated, small (<5 cm) lesion

with a white to grey aspect and alternating yellow and brown areas. In contrast, diffuse-TGCT

involves a large part or all of the synovial lining with either a typical villous pattern (intra-

articular) or a multi-nodular appearance (extra-articular), including a diverse colour pattern,

varying from white-yellow to brown-red areas. The diffuse-type shows an infiltrative growth

pattern. Microscopically, both types contain an admixture of mononuclear cells (histiocyte-like

and larger cells) and multinucleated giant cells, lipid-laden foamy macrophages (also known as

xanthoma cells), siderophages (macrophages including hemosiderin-depositions), stroma with

lymphocytic infiltrate and some degree of collagenization (figure 4)1, 2.

Figure 4 Tenosynovial Giant Cell Tumours contain an admixture of mononuclear cells, multinucleated giant

cells, foam macrophages and siderophages.

siderophages

mononuclear cells

giant cell

foam macrophage


21

1clinical presentation

TGCT affecting small joints, both fingers and toes, usually presents as localized-TGCT. In large

joints, excluding digits, both localized- and diffuse-TGCT are seen. The diffuse-type mainly

affects weight-bearing joints, predominantly the knee (75%)1, 2, 4. TGCT incidence is based on one

single US-county study in 1980, that reported an incidence of 9 and 2 per million person-years

for localized- (including digits) and diffuse-TGCT, respectively23. Male:female ratio is about 1:1.5

for both types. The mean age at the time of diagnosis lies between 30 and 50 years1, 2, 4. Typically,

patients primarily present with pain and swelling of the associated joint (figure 1a). Additional

symptoms might be limited range of motion, stiffness, instability, giving way and locking

complaints5. Time to definitive diagnosis is often prolonged, on average 4.4 years, due to these

unspecific symptoms and the rarity of the disease4, 24, 25. As TGCT is not lethal, overall survival

is similar to the general population. Diffuse-TGCT frequently becomes a debilitating chronic

illness; therefore joint function and quality of life should be assessed as disease-outcome3, 5, 26, 27.

radiology

In daily practice, an X-ray imaging of the affected joint is frequently performed as a first line

imaging. Degenerative changes and effusion may be present but are nonspecific, and could

also be noticed on computed tomography (CT). Magnetic resonance (MR) imaging is the most

distinctive imaging technique7, 8, 28-30. MR imaging reveals nodular (localized-type) or villous

(diffuse-type) proliferation of synovium, including associated joint effusion. On T1- and T2-

weighted fast spin echo and other fluid sensitive sequences, lesions demonstrate predominantly

intermediate to low signal intensity (dark). After intravenous administration of Gadolinium-

chelate, TGCT shows heterogeneous enhancement. Hemosiderin deposits are frequently seen,

but occur also in other entities31. This degraded hemoglobin deposits cause local changes in

susceptibility (‘blooming effect’) on gradient echo sequences, resulting in low signal intensity

areas that are larger than the anatomical substrate (figure 1b). No substantial change in signal

intensity is detected when comparing the localized- and diffuse-types7, 28. Differential diagnosis

based on MR imaging includes hemophilia, synovial hemangioma, rheumatoid pannus, amyloid

arthrophy and desmoid fibromatosis.

22

Chapter one

treatment modalities

The current standard of care is still surgical resection of the tumour, either arthroscopically

or with an open resection (figure 5), in order to: 1. reduce pain, stiffness, and joint destruction

caused by the disease process; 2. improve function; and 3. minimize the risk of recurrence.

Depending on the extensiveness of the disease, complete resection is frequently impossible,

especially in diffuse-TGCT. Some reports consider arthroscopic management of TGCT superior to

open surgery, because of less morbidity and a shorter recovery period32-36. Standard arthroscopy

of the knee using the anteromedial and anterolateral approaches however, does not allow

surgical access to all areas where diseased tissue could be present. A systematic review showed

lower recurrence rates for open synovectomy (average 14%, maximum 67%) compared to

arthroscopic synovectomy (average 40%, maximum 92%) in diffuse-TGCT37. A randomized

controlled trial for arthroscopic synovectomy versus open synovectomy or surgical treatment

versus targeted therapy is not (yet) performed.

Figure 5 (right page) Example of the surgical technique of an open synovectomy in localized-

TGCT. An 8-year-old boy presented at the outpatient clinic with intermittent complaints of pain and

swelling of his left knee of more than 12 months. These progressive debilitating symptoms were

not sufficiently reduced by paracetamol and have led to school absenteeism. In the outpatient

clinic, swelling was not objectified without limitation in range of motion and palpation was diffusely

pressure painful. X-ray imaging did not show abnormalities. a. A sagittal T1-weighted MR imaging

after intravenous administration of Gadolinium-chelate, revealed a well-circumscribed lesion

on the posterior knee compartment. The T1-weighted and Proton Density MR scan (not shown

here) revealed a lesion of low intensity. Despite the young age of the boy, a localized-TGCT was

suspected. An open resection was planned, because of debilitating symptoms. b. A small lazy-C-

incision was performed on the posterior, lateral side of the left knee. This approach and surgical

window was chosen because of the lateral tumour localization. After opening the crural fascia,

the saphena parva vene, the suralis cutaneous medius nerve, the tibialis nerve and the peroneus

nerve were identified. Lateral gastrocnemius muscle was partially released, because of lateral

localization of the tumour, without compromising the neurovascular bundle. c & d. The capsule

overlying the tumour was partially released. A yellow-brown tumourous aspect showed and

could be resected en bloc from the posterior cruciate ligament where it generally pedicles from.

e. The entire localized-TGCT was excised. f. Minimal invasive techniques can be used to prevent post-

operative complaints such as stiffness. After histological examination, TGCT diagnosis was confirmed.


23

1

a b

c d

e f

24

Chapter one

In patients with extensive and/or recurrent TGCT, other available treatment modalities include

radiation synovectomy with 90yttrium38, external beam radiation therapy39-41, and cryosurgery42.

Their therapeutic value has only been assessed in retrospective, mostly single center series and

their long-term side effects and complications are poorly described.

Discovery of the CSF1-CSF1R pathway in the pathogenesis of the tumour contributed to trials

with targeted therapy. At present extensive or recurrent diffuse-TGCT is also treated with non-

selective CSF1 inhibitors such as nilotinib and imatinib43, 44; selective CSF1 inhibitors such as

pexidartinib, emactuzumab, cabrilazimab; or monoclonal antibody such as MSC11045-48. Long-

term efficacy data have not yet been reported with these newer agents. Emactuzumab showed

an overall response rate of 86% and a rate of disease control of 96%, including a significant

functional and symptomatic improvement (median follow up 12 months)45. The preliminary

results for cabiralizumab are consistent, with radiographic response and improvement in

pain and function in five out of 11 patients (45%)46. Pexidartinib had an overall response rate

of 52% (all patients had a partial response) and a rate of disease control of 83%. Responses

were associated with an improved joint function (median duration of response exceeded eight

months)48.

tgct in animals

TGCT affects both humans and animals. Case-reports of cats, dogs, horses, a European lynx and

a reticulated giraffe are described49-55. Adequate diagnosis is animals is even more challenging,

due to its rarity, unspecific symptoms and the absence of a verbal patient history. MR scans

are infrequently performed. When animals present with debilitating symptoms of this tumour,

extreme measures as joint amputation or euthanasia are more common.


25

1aim of thesis

Treatment of the often debilitating chronic illness, tenosynovial giant cell tumours (TGCT) of

large joints, is challenging. This thesis aims to find better treatment modalities for this disease

by evaluating the pathophysiology, biological behavior, diagnosis and quality of life. Sufficient

data for evaluation of the rare disease TGCT was established through collaboration with the

RadboudUMC and additionally with 31 international sarcoma centers.

Foremost, this thesis aims to create awareness for TGCT and to improve medical care. It evaluates

different aspects of this heterogeneous neoplasm and addresses currently existing lacunas

concerning disease incidence, histopathologic- and hormonal characteristics, disease severity

stratification and pediatric disease burden. Moreover, this thesis addresses long-term effects

of systemic targeted treatment and assessment of health-related quality of life after treatment

in TGCT patients. Lastly, this thesis presents the largest global individual data study of TGCT for

both localized- and diffuse-type TGCT.

outline of thesis

In chapter 2 we performed nationwide incidence calculations upon TGCT, since no incidence

study was reported past 1980. Radiologically and clinically, localized- and diffuse-TGCT are two

different entities. However, genetically and histopathologically they are identical. Chapter 3

correlates the biological behaviour of TGCT in the knee at a molecular level.

In the patient-population of localized- and diffuse-TGCT, different disease extent exist. Therefore,

chapter 4 focuses on the establishment of a TGCT severity classification, sub-classifying both

localized- and diffuse-type TGCT into two more distinct subtypes.

The clinical behaviour between TGCT patients differs greatly. In chapter 5 we explore the

influence of female sex hormones on the experienced TGCT-related symptoms.

Many case-series of TGCT in adults are described, whereas TGCT is only incidentally reported in

children. Chapter 6 evaluates differences in TGCT presentation between adults and children.

Relatively small and heterogeneous case-series emphasize the importance of a large-scaled study.

In chapter 7 and chapter 8, an international multicentre study in 31 international sarcoma

centres is described. This study explores risk factors for TGCT of large joints in 941 localized- and

26

Chapter one

1192 diffuse-type TGCT patients. Results of this study are crucial to the treatment possibilities

and prognosis of this rare entity.

Since a decade, targeted therapies are used in TGCT; however long-term results are still lacking.

In chapter 9, we evaluated the long-term efficacy of imatinib mesylate, a targeted therapy

blocking the Colony Stimulating Factor 1 (CSF1) receptor, in patients with advanced TGCT.

In a benign disease, not only oncologic outcomes are of interest. Of utmost importance is quality

of life for patients bearing this chronic disease. Chapter 10 evaluates the quality of life and joint

function after surgical treatment and chapter 11 assesses the patient perspective on daily life

with TGCT by crowdsourcing.

To emphasize the impact of a disease considered benign, extreme measures like above knee

amputation are described in chapter 12 as final treatment for TGCT.

Finally, a summary of this thesis is provided in chapter 13. Conclusions, clinical implications and

future perspectives for the subject of this thesis are discussed in chapter 14.


27

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inci

den

ce Higher incidence

rates than previously known

in tenosynovial giant cell tumours

chap

ter

two

a nationwide study in the netherlandsM.J.L. Mastboom1, F.G.M. Verspoor2, A.J. Verschoor3, D.

Uittenbogaard1, B. Nemeth4, W.J.B. Mastboom5, J.V.M.G. Bovée6, P.D.S. Dijkstra1, H.W.B. Schreuder2, H. Gelderblom3,

M.A.J. van de Sande1, TGCT study-group*Acta Orthop. 2017 Dec;88(6):688-694

1 Orthopaedic Surgery, Leiden University Medical Centre, Leiden, the Netherlands

2 Orthopaedic Surgery, Radboud University Medical Centre, Nijmegen, the Netherlands

3 Medical Oncology, Leiden University Medical Centre, Leiden, the Netherlands

4 Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands

5 Oncology Surgery, Medical Spectrum Twente, Enschede, the Netherlands

6 Pathology, Leiden University Medical Centre, Leiden, the Netherlands

*TGCT study-group:

G.R. Schaap, W.J. Kleyn Molekamp, S.T. Hokwerda, P. van der Woude, M. Henket, S.E. Brandt, J. van de Breevaart

Bravenboer, L.A. Lisowski, P. van der Zwaal, J.M.G.T. Jenner, J.A. Jansen, A. de Gast, H.J. Noten, D.E. Meuffels, T. Gosens,

R. Krips, D.T. Mensch, P.H.J. Bullens, R. Onstenk, F.L. Van Erp Taalman Kip, A.P. van Noort-Suijdendorp, C.H. Geerdink,

D.M.J. Dorleijn, H.H. Kaptijn, M.W. Bloembergen, O.P.P. Temmerman, W.P. Zijlstra, T.D. Berendes, M. van den Besselaar,

U.T. Timur, M.A. Witlox, M.R. Krijnen, P.C. Konings, B.R. Chander, F.C.W. Slootmans, D.J. Wever, D. Haverkamp, R.E.A.M.

Zwartelé, E.M. Nelissen, K.G. Auw Yang, R. de Haan, P.C. Jutte, D.B.F. Saris, S.F. de Boer, R.J. de Raadt, C.P. Schönhuth,

J.G.A. Amaya, R.J. Hillen, A.J.H. Vochteloo, B.G.W. Daalmans, P.C. Kaijser Bots, W.L.W. van Hemert

Incidence rates in tenosynovial giant cell tumours

33

2abstract

Background and purpose

Tenosynovial Giant Cell Tumours (TGCT) are rare, benign tumours, arising in synovial lining of

joints, tendon sheaths or bursae. 2 Types are distinguished: localized-, either digits or extremity,

and diffuse lesions. Current TGCT incidence is based on 1 single US-county study in 1980, with

an incidence of 9 and 2 per million person-year in localized- (including digits) and diffuse-

TGCT, respectively. We aim to determine nationwide and worldwide incidence rates (IR) in TGCT

affecting digits, TGCT localized-extremity and TGCT diffuse-type.

Material and methods

Over a 5-year period, the Dutch Pathology Registry (PALGA) identified 4503 pathology reports on

TGCT. Reports affecting digits were solely used for IR-calculations. Reports affecting extremities,

were clinically evaluated. Dutch IRs were converted to world population IRs.

Results

2815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type TGCT were identified.

Dutch IR in digits, localized extremity and diffuse-type was 34 (95% CI 33-35), 11 (95% CI 11-

12) and 5 (95% CI 4-5) per million person-years, respectively. All 3 groups showed a female

predilection and highest number of new cases in age-category 40-59 years. Knee-joint was

most often affected: localized-extremity (46%) and diffuse-type (64%), mostly treated with

open-resection: localized (65%) and diffuse (49%). Reoperation rate due to local recurrence for

localized-extremity was 9%, diffuse-TGCT 23%.

Interpretation

This first nationwide study and detailed analyses of IRs in TGCT estimated a worldwide IR in

digits, localized-extremity and diffuse-TGCT of 29, 10 and 4 per million person-years, respectively.

Recurrence rate in diffuse-type is 2.6 times higher, compared with localized-extremity. TGCT is

still considered a rare disease; however, it is more common than previously understood.

34

Chapter two

Background

Tenosynovial Giant Cell Tumours (TGCT) are a rare entity, affecting generally young patients

(below the age of 40 years), with an equal sex distribution. The World Health Organisation (WHO)

classification of Tumours of Soft Tissue and Bone (2013) distinguishes 2 TGCT-types: localized and

diffuse lesions1, 13. Microscopically the 2 types show no clear difference. However, on Magnetic

Resonance Imaging (MRI) discrimination between these types is made2.

The localized-type was previously described as Giant Cell Tumour of Tendon Sheath, nodular synovitis

or localized Pigmented VilloNodular Synovitis (PVNS). The typical macroscopic aspect is a well

circumscribed, small (among 0.5 to 4 centimetres) usually lobulated lesion, with white to grey, yellow

and brown mottled areas1. Based on anatomical site of the localized-type tumour, differentiation is

made into a group affecting digits and a group occurring in and around larger joints3, 4. TGCT affecting

digits is defined as a localization distal to metacarpal or metatarsal bones; localized TGCT-extremity is

defined as all sites near joints proximal and including metacarpal- and metatarsal-joints.

In localized-TGCT, most lesions are found in the digits of hand and feet (Figure 1). The majority

of these lesions arise from the tendon sheath and less frequently from synovial lining of digital

joints. Common treatment is marginal excision5, 6. A systematic review showed a recurrence rate

of 15%, after an average follow-up of 37 to 79 months7. Fewer localized TGCT lesions are found

around larger joints, they originate from synovial lining, tendon sheaths or bursae (Figure 2). The

preferred treatment of these lesions is marginal excision by an arthroscopic or by open approach5,

6. A systematic review reported an average recurrence rate of 6% after arthroscopic resection and

4% after open resection (with variable follow-up)8.

The diffuse-type TGCT; previously called diffuse Pigmented VilloNodular Synovitis (PVNS) or

Synovitis (Villo)nodularis Pigmentosa (SVP), is a more destructive and locally aggressive tumour

(figure 3). Diffuse-TGCT is defined by the presence of an infiltrative soft tissue mass along synovial

lining, showing villous projections of the proliferated synovial membrane, with or without

involvement of the adjacent joint or other structures. Macroscopically, the diffuse-type affects a

large part of synovial lining and has a multinodular, multi-coloured appearance, including white,

yellow and rust-coloured areas1. 75% are located around the knee-joint8. Current treatment


35

2

Figure 1 MRI of TGCT localized-type, affecting digits - A 43 year old male patient with a well circumscribed

tumour in the proximal phalanx of the third digit of the right hand. a. A coronal T1-weighted MRI after

intravenous contrast injection. b. A clear coronal T1 weighted MRI without intravenous contrast injection.

a b

Figure 2 MRI of TGCT localized-type, extremity - Sagittal T1 weighted turbo spin echo MRI of a 47 year old

female patient, affecting her right knee. A well circumscribed lesion in Hoffa’s fat pad is seen. a. Proton density

weighted MRI. b. Pre-saturation inversion recovery MRI.

a b

36

Chapter two

is surgical excision5, 6, 9. However, it is often difficult to perform a marginal excision. Average

recurrence rates after arthroscopy are 40% and after open resection 14%, with variable follow-up

times8. In extensive disease, peri-operative radiotherapy might reduce recurrence rate10, 11. Patients

with (multiple) recurrences experience impaired quality of life12.

According to the WHO-classification of 2002 and 2013, the Incidence Rate (IR) in TGCT is not exactly

known1, 13. Current TGCT IRs are based on 1 single US-county study completed in 1980, with an IR

of 9 and 2 per million person-year in localized- (including digits) and diffuse-TGCT, respectively14.

Verschoor et al. (2015) performed the initial nationwide registry based study on giant cell

containing tumours and calculated an overall IR for TGCT of 50 per million per year. Discrimination

between localized and diffuse disease was not possible as additional clinical information was

lacking. The difference in biological behaviour, however, demands for further stratification of this

general IR in the 3 different TGCT-groups. Therefore, we aimed to estimate the worldwide (WHO-

standardized) TGCT IR by investigating clinical data of affected joints, sex differences, 10 year age

specific categories, initial treatments, follow-up and recurrences rate at individual patient level

through extensive additional data collection at participating hospitals.

Figure 3 MRI of TGCT diffuse-type. A 23 year old male patient with an extensive proliferative synovial process

around both cruciate ligaments, dominating the anterior and posterior knee compartments, intra- and extra-

articular. Inside suprapatellar pouch and Baker’s cyst a blooming villonodular aspect shows typical iron

depositions. a. Sagittal proton density weighted turbo spin echo MRI. b. Sagittal T2 weighted fast field echo MRI.

a b


37

2material and methods

A search in PALGA, the non-profit nationwide network and registry of histo- and cytopathology

in The Netherlands was performed15. To find all patients with Tenosynovial Giant Cell Tumours,

between January 2009 and January 2014, search terms ‘Tenosynovial Giant Cell Tumour’, ‘Pigmented

Villonodular Synovitis’ and a variety of synonyms were used, either as a code or as free text16, see

supplementary data. Received pathology-reports provided limited and anonymous information

on sex, age, date of tissue removal and conclusion of the pathology report. In these reports,

definitive diagnosis was frequently provided, however information on (localized/diffuse) type and

affected joint was only sparsely available. Therefore, further investigation of additional clinical and

radiological data was necessary. Reports with TGCT affecting digits were solely used for calculating

incidence rate (for TGCT-digits) and not further investigated clinically. PALGA interlinked 1941

pathology-reports to 95 original Dutch hospitals. Departments of pathology received a request to

collaborate in this nationwide study. After approval, personal hospital identifiers were obtained and

concerned departments (mostly orthopaedics and general surgery) were invited to confirm TGCT

diagnosis and add detailed information on TGCT-type, affected joint, sex, age at first histologically

proven TGCT, primary treatment, total surgeries related to TGCT, date of last follow-up and follow-up

status. Clinical and radiographic data were derived from medical files. Data were kept anonymously.

75 of 95 attributed hospitals collaborated, including all specialized and academic centres.

Clinical evaluation started with 1941 eligible TGCT cases. In 1576 (81%) cases, diagnosis was

confirmed. 253 Reports were determined to be in digits and amended in digits-group. For included

TGCT extremity cases (n 1323), incomplete evaluated clinical data were imputed for unknown

data on TGCT-type (n=393), affected joint (n=101), sex (n=52), age (n=54) and treatment (n=484),

using multiple imputation techniques. 10 Datasets were imputed, results were pooled according

to standard Rubin’s rules17. All imputed data were checked for errors. Finally, 1323 patients with

histological proven TGCT were included (figure 4).

In addition to the 2562 patients with TGCT affecting digits which were already identified based on

the pathology reports, 253 additional patients with TGCT affecting digits were discovered during

clinical data evaluation. 2815 TGCT patients affecting digits were identified (2649 fingers, 119 toes,

47 finger or toe), but not investigated in detail.

38

Chapter two

Reoperation rate due to local recurrence was defined as surgery for recurrent TGCT, based on

additional pathology reports in the same patient, at least 6 months after initial surgery until

January 2015 (date of PALGA-search).

Statistics

The Statistical Package for Social Sciences statistics (SPSS) version 23 was used for analyses.

The IR was separately estimated for TGCT localized-, either digits or extremity, and diffuse-type

TGCT per year, by using the number of histologically proven TGCT as numerator and the sum

of individual person-years for The Netherlands as the denominator. IRs were reported for the

overall study period, by calendar year, and stratified on type, affected joints, sex and 10-years age

categories (age at TGCT diagnosis). The Central Bureau of Statistics (CBS) provided information

on Dutch population during the examined period.

Overall worldwide IRs were obtained by standardizing Dutch IRs to global IRs by using the

direct method, applying age-specific IRs in each 10-year age group to the world WHO standard

population (http://seer.cancer.gov). Estimates of IRs were reported with 95% Confidence

Intervals (CI). Patient demographics were reported as counts and percentages for categorical

variables and as medians and interquartile ranges (IQR) for continuous variables. The Kaplan

Meier method was used to evaluate reoperation due to local recurrence free survival at 2- and

at 5-year.

Ethics, funding, and potential conflict of interest

Research is performed in accordance with the ethical standards in the 1964 Declaration of

Helsinki. As this study does not involve subject-related research, it is not covered by Dutch law on

human subjects research. This study is approved by the Institutional review board (CME) from our

institution (registration number G16.024, 22 April 2016). In collaboration of physicians of the TGCT

study group, and in special collaboration with Radboud University Medical Centre and Medical

Spectrum Twente, data collection was performed. Data capturing and analyses was performed

in the Leiden University Medical Centre. No funding or benefits were received, by none of the

authors. There is no conflict of interest by any of the authors regarding this manuscript.


39

2

Figure 4 Inclusion flowchart *Localized-TGCT affecting extremities, excluding digits

2562 digits

4503 pathology reports

1941 extremity

clinical evaluation253 digitsexcluded

39 double reports326 not TGCT

1323 TGCT reports

2815 digits-TGCT 933 localized-TGCT* 390 diffuse-TGCT*

40

Chapter two

Table 1 Incidence rates (IRs) of localized- and diffuse-type TGCT in The Netherlands:

overall, by calendar year 2009-2013, sex and age-categories.

Person-years

Localized TGCT – digits Localized TGCT – extremity Diffuse TGCT

New cases* IR** New cases* IR** New cases* IR**

Overall 83,226,498 2815 33.8 (33 - 35) 933 11.2 (11 - 12) 390 4.7 (4 - 5)

Calendar year

2009 16,485,787 578 35.1 (32 - 38) 192 11.7 (10 - 13) 73 4.4 (4 - 6)

2010 16,574,989 561 33.8 (31 - 37) 183 11.0 (10 - 13) 82 5.0 (4 - 6)

2011 16,655,799 580 34.8 (32 - 38) 176 10.6 (9 - 12) 78 4.7 (4 - 6)

2012 16,730,348 563 33.6 (31 - 37) 188 11.2 (10 - 13) 77 4.6 (4 - 6)

2013 16,779,575 533 31.8 (29 - 35) 194 11.6 (10 - 13) 80 4.8 (4 - 6)

Sex

Female 42,032,934 1698 (60) 40.4 (39 - 42) 544 (58) 12.9 (12 - 14) 236 (61) 5.6 (5 - 6)

Male 41,193,564 1117 (40) 27.1 (26 - 29) 389 (42) 9.4 (9 - 10) 154 (39) 3.7 (3 - 4)

Age at diagnosis

0-9 9,528,271 13 (0) 1.4 (1 - 2) 6 (1) 0.6 (0 - 1) 2 (0) 0.2 (0 - 1)

10-19 10,012,994 98 (3) 9.8 (8 - 12) 57 (6) 5.7 (4 - 7) 26 (7) 2.6 (2 - 4)

20-29 10,178,289 259 (9) 25.4 (23 - 29) 108 (11) 10.6 (9 - 13) 49 (13) 4.8 (4 - 6)

30-39 10,673,194 411 (15) 38.5 (35 - 42) 169 (18) 15.8 (14 - 18) 62 (16) 5.8 (5 - 7)

40-49 12,894,743 650 (23) 50.4 (47 - 54) 211 (23) 16.4 (14 - 19) 70 (18) 5.4 (4 - 7)

50-59 11,456,662 704 (25) 61.5 (57 - 66) 193 (21) 16.9 (15 - 19) 71 (18) 6.2 (5 - 8)

60-69 9,466,681 503 (18) 53.1 (49 - 58) 133 (14) 14.0 (12 - 17) 58 (15) 6.1 (5 - 8)

70-79 5,680,080 155 (6) 27.3 (23 - 32) 41 (4) 7.2 (5 - 10) 37 (9) 6.5 (5 - 9)

80-89 2,860,556 22 (1) 7.7 (5 - 12) 15 (2) 5.2 (3 - 9) 15 (4) 5.2 (3 - 9)

*New cases: number of cases, %. **IR: Incidence rate per million person-years (95% CI).


41

2Table 1 Incidence rates (IRs) of localized- and diffuse-type TGCT in The Netherlands:

overall, by calendar year 2009-2013, sex and age-categories.

Person-years

Localized TGCT – digits Localized TGCT – extremity Diffuse TGCT

New cases* IR** New cases* IR** New cases* IR**

Overall 83,226,498 2815 33.8 (33 - 35) 933 11.2 (11 - 12) 390 4.7 (4 - 5)

Calendar year

2009 16,485,787 578 35.1 (32 - 38) 192 11.7 (10 - 13) 73 4.4 (4 - 6)

2010 16,574,989 561 33.8 (31 - 37) 183 11.0 (10 - 13) 82 5.0 (4 - 6)

2011 16,655,799 580 34.8 (32 - 38) 176 10.6 (9 - 12) 78 4.7 (4 - 6)

2012 16,730,348 563 33.6 (31 - 37) 188 11.2 (10 - 13) 77 4.6 (4 - 6)

2013 16,779,575 533 31.8 (29 - 35) 194 11.6 (10 - 13) 80 4.8 (4 - 6)

Sex

Female 42,032,934 1698 (60) 40.4 (39 - 42) 544 (58) 12.9 (12 - 14) 236 (61) 5.6 (5 - 6)

Male 41,193,564 1117 (40) 27.1 (26 - 29) 389 (42) 9.4 (9 - 10) 154 (39) 3.7 (3 - 4)

Age at diagnosis

0-9 9,528,271 13 (0) 1.4 (1 - 2) 6 (1) 0.6 (0 - 1) 2 (0) 0.2 (0 - 1)

10-19 10,012,994 98 (3) 9.8 (8 - 12) 57 (6) 5.7 (4 - 7) 26 (7) 2.6 (2 - 4)

20-29 10,178,289 259 (9) 25.4 (23 - 29) 108 (11) 10.6 (9 - 13) 49 (13) 4.8 (4 - 6)

30-39 10,673,194 411 (15) 38.5 (35 - 42) 169 (18) 15.8 (14 - 18) 62 (16) 5.8 (5 - 7)

40-49 12,894,743 650 (23) 50.4 (47 - 54) 211 (23) 16.4 (14 - 19) 70 (18) 5.4 (4 - 7)

50-59 11,456,662 704 (25) 61.5 (57 - 66) 193 (21) 16.9 (15 - 19) 71 (18) 6.2 (5 - 8)

60-69 9,466,681 503 (18) 53.1 (49 - 58) 133 (14) 14.0 (12 - 17) 58 (15) 6.1 (5 - 8)

70-79 5,680,080 155 (6) 27.3 (23 - 32) 41 (4) 7.2 (5 - 10) 37 (9) 6.5 (5 - 9)

80-89 2,860,556 22 (1) 7.7 (5 - 12) 15 (2) 5.2 (3 - 9) 15 (4) 5.2 (3 - 9)

*New cases: number of cases, %. **IR: Incidence rate per million person-years (95% CI).

42

Chapter two

results

During a 5-year period; 2815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type

TGCT were identified. TGCT affected digits 3 and 7 times more often compared to localized-extremity

and diffuse-TGCT, respectively. Dutch TGCT IRs were 34 (CI 33 - 35) in TGCT affecting digits, 11 (CI 11

- 12) in localized-type extremity TGCT and 5 (CI 4 - 5) in diffuse-type TGCT per million person-years.

Median age for TGCT affecting digits was 49 (IQR 38-59) years, for localized-extremity type 45 (IQR

34-56) years and diffuse-TGCT 47 (IQR 32-61) years. Male-female ratio was about 1:1.5 for any type.

Table 1 shows IRs per million person-years by calendar years 2009 up to and including 2013, sex

and 10 year age-specific categories of the 3 different TGCT-groups. In these 3 groups: IRs over

disaggregated years were quiet similar, female IR were slightly higher compared to male IRs and the

majority of new cases were seen in age-categories 40-49 and 50-59 years.

In 2015, The Netherlands counted 16,900,726 inhabitants. According to calculated IR; 571 new TGCT

affecting digits, 189 new localized-extremity and 79 new diffuse-TGCT patients were diagnosed

in 2015. The estimated standardized worldwide IRs were 29, 10 and 4 per million person-years for

respectively localized-digits, localized-extremity and diffuse-TGCT.

As TGCT affecting digits were not clinically investigated, following results were based on localized-

extremity and diffuse-type. The majority of TGCT cases affected the knee-joint; 46% and 64% in localized-

and diffuse-TGCT respectively (figure 5), followed by the hand- and wrist-joint in localized-type and the

ankle- and hip-joint in diffuse-type TGCT. Sex distribution per affected joint was comparable.

The initial TGCT treatment plan was open resection in 65% and 49% in localized- and diffuse-

lesions, respectively (figure 6). TGCT was reported as an incidental finding during endoprosthetic

replacement in 60 procedures.

According to the clinical charts, the majority of patients were lost to follow-up in both types (71%

in localized- and 55% in diffuse-TGCT). Therefore, we decided to base recurrence rates on additional

surgeries (defined by a second pathology report documenting recurrence of TGCT in PALGA). By

evaluating the municipal personal records database (Gemeentelijke BasisAdministratie (GBA)) for


43

2all patients, 8 patients (7 localized- and 1 diffuse-TGCT) deceased at time of evaluation and were

censored at time of death when no second surgery was performed.

Reoperation rate due to local recurrence, calculated as a percentage from all TGCT patients, in localized-

TGCT was 9% and in diffuse-TGCT 23%. Reoperation free survival curves for localized- and diffuse-TGCT are

shown in figure 7. In localized-extremity, reoperation free survival at 2- and at 5-years was 90% and 83%,

respectively. In diffuse-type, reoperation free survival at 2- and at 5-years was 77% and 49%, respectively.

Only a minority (12%) of TGCT patients were primarily treated in a tertiary oncology centre: 9% of

localized-type (excluding digits) and 18% of diffuse-type.

1%

2%

1%12%24%

46%

5%

6%

localized-TGCT diffuse-TGCT

3%

2%

9%5%2%

64%

10%

4%

Figure 5 Skeleton, showing affected TGCT localization (fingers and toes excluded).

3% in localized-type and 1% in diffuse-type is classified as ‘other’ .

44

Chapter two

Figure 7 Reoperation due to local recurrence free survival curve in localized-extremity and diffuse-TGCT

(Kaplan Meier), excluding digits. Time zero is time of primary surgery. 8 Patients died and were censored at

time of death if a reoperation had not occurred.

Figure 6 Bar graph initial treatment for TGCT affecting extremities in The Netherlands, excluding digits.

Localized

perc

enta

ge

Diffuse

Years after index operation

Reop

erat

ion

free

sur

viva

l (%

)

Arthroscopic resection

Open resection

(Tumour) prosthesis

Wait and see

localized

diffuse


45

2discussion Microscopically localized-extremity and diffuse-TGCT are identical1. A distinction is made

between localized-digits and localized-extremity, based on anatomical location and histological

differences3, 4. TGCT affecting digits are characterized as multiple, small (average 1 centimetres)

nodules surrounded by a thin fibrous capsule, originating in synovial tissue of tendon sheaths or

small joints of digits, with a small number of cleft-like spaces and thick bundles of collagenous

tissue, showing rarely inflammatory cells. On the contrary, TGCT localized-extremity lesions are

typically single, relatively large (average 2 centimetres) lesions covered by 1 or more layers of

synovial cells, intra-articular, showing large or numerous pseudoglandular spaces sometimes

filled with foam cells and showing more inflammatory cells than digits3.

Because of the rarity of the disease, current TGCT literature contains predominantly retrospective,

relatively small cohort studies, including heterogeneous data4. 2 previous studies described

TGCT incidence: Myers and Masi (1980) reported 117 new cases of localized- (including digits)

and 49 new cases of diffuse-type TGCT between 1960 and 1976, resulting in an IR of 9 per million

person-years for localized- and 2 per million person years for diffuse-type TGCT. A single hospital

study was performed by Monoghan et al. (2001) and showed an IR of 20 new cases per million

per year between 1990 and 1997 for localized-type TGCT (including digits). Compared to the

initial US-county study14, our study showed a 5-fold higher IR in localized-type (combining

localized-digits and localized-extremity), and a more than 2.6 fold higher IR in diffuse-type. This

difference could be attributed to our nationwide coverage, our registry based-clinically verified

character and because of increased knowledge about the disease.

Localized- and diffuse-lesions are distinguished clinically and on MRI. To investigate these

lesions separately, clinical and radiological confirmation is of utmost importance. Treatment

in localized-TGCT affecting digits or extremity is mostly 1 single excision. In contrast, multiple

mutilating surgeries are often required for diffuse-type TGCT, with a continuous risk of

recurrences. In an effort to find all TGCT patients, our search included specific pathology codes

for TGCT and both TGCT and synonyms of TGCT as free text (Appendix). Therefore, cases with

‘synovitis’ or differential diagnostic TGCT were represented in our search. In addition, PALGA

data is based on input of physicians and sometimes lacks specificity. For instance affected joint:

46

Chapter two

‘upper extremity’, ‘hand’ or ‘wrist’ could all turn out, after clinical evaluation, to be affected digits.

In our search, 1941 patients were clinically evaluated and 1323 ascertained histologically proven

TGCT extremity cases were included. Consequently, only 68% of eligible TGCT patients had

histologically proven TGCT of the large joints. Without clinical TGCT-confirmation, the estimated

IR would have been much higher.

Despite our large number of patients with lack of follow-up, reoperation rates due to local

recurrence were described, based on additional surgeries, defined by a second pathology

report documenting recurrence of TGCT in PALGA (up to January 2015, date PALGA-search

was performed). Recurrences without treatment (no additional pathology report) were not

included, therefore reoperation rate due to recurrence is not identical to recurrence rate.

However, compared to literature, we found comparable average recurrence rates for localized-

TGCT-extremity (9%) and for diffuse-type (23%)8. As local recurrence might develop years after

initial surgery18, and PALGA provided pathology reports with a maximum of 7 years after initial

surgery, underestimation of the true recurrence free survival is likely.

There are some limitations to this study. Determined IR may be exposed to under- or

overestimation. Primarily, our calculated IR could be slightly underestimated, because our study

is based on a search in PALGA, the nationwide network and registry of histo- and cytopathology

in The Netherlands15. TGCT patients without a biopsy or treatment are not represented in this

pathology based cohort.

Second, our IR in localized-extremity and diffuse-type could be marginally over- or

underestimated, because 21% of eligible TGCT patients was not clinically evaluated and

therefore imputed. Analyses with and without imputed data were comparable. PALGA identified

1941 eligible TGCT patients, scattered over 95 Dutch hospitals. Regarding different hospital-

boards, different concerning departments (pathology, orthopaedics, general surgery) and

different local legislations, it was challenging to evaluate all eligible TGCT patients.

Third, clinical distinction between localized-extremity and diffuse-type TGCT is difficult,

especially for clinicians not familiar with this rare disease19.

Subsequently, an overestimation of IR in TGCT localized-digits might be present. IR of digits is

solely based on PALGA-registry numbers, in contrast to localized-extremity and diffuse-TGCT IRs


47

2which were clinically evaluated.

Global IRs were estimated by using a direct standardization approach (http://seer.cancer.gov).

Even though this is a widely accepted method, there is no adjustment for other influences in

global structure or possible risk factors in TGCT.

To calculate prevalence rates, follow-up time and status is important. Majority of our investigated

patients lacked in clinical chart follow-up. It seemed unfair to estimate TGCT prevalence rates as

the proportion of TGCT patients alive at the end of 2013 and diagnosed with TGCT: this assumes

TGCT to not resolve and not to be cured.

In The Netherlands, traditionally, larger orthopaedic clinics have been treating TGCT or diagnosed

TGCT as an incidental finding during arthroscopy or endoprosthetic replacement. When (severe)

complaints occur, patients are commonly referred to specialized tertiary sarcoma centres. In this

study, we investigated primary patients to calculate incidence rate. No centralization of care

of TGCT in these primary patients is shown, with only a minority of 12% primarily treated in a

tertiary oncology centre. Remarkably, only 18% of diffuse-TGCT was primarily treated in tertiary

oncology centres.

In summary, this study is the first nationwide study and detailed analyses of IRs in TGCT. IRs

for TGCT of digits, localized-type-extremity and diffuse-type were calculated using additional

hospital record evaluation of patients originally selected from a nationwide pathology registry.

The worldwide estimated incidence rate in digits, localized-extremity and diffuse-TGCT is 29,

10 and 4 per million person-years, respectively. Despite high clinical variability in localized-

extremity and diffuse-lesions, both types show a predilection for the knee-joint, slight

predisposition in female patients, median age around 47 years at first treatment and primarily

treated with an open resection. Recurrence rate in diffuse-type is 2.6 times higher, compared to

localized-type extremity. TGCT is still considered a rare disease, however, more common than

previously understood.

Supplementary data

An appendix is available as supplementary data in the online version of this article,

http://dx.doi.org/10.1080/17453674.2017.1361126

48

Chapter two

references

1. de St. Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour, localized type/diffuse type. In: Fletcher

CD, Bridge JA, Hogendoorn PC, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. 5. 4th ed.

Lyon: IARC Press; 2013. p. 100-3.



3. Ushijima M, Hashimoto H, Tsuneyoshi M, Enjoji M. Giant cell tumor of the tendon sheath (nodular tenosynovitis). A

study of 207 cases to compare the large joint group with the common digit group. Cancer. 1986;57(4):875-84.

4. Chiari C, Pirich C, Brannath W, Kotz R, Trieb K. What affects the recurrence and clinical outcome of pigmented

villonodular synovitis? Clin Orthop Relat Res. 2006;450:172-8.



6. Verspoor FG, van der Geest IC, Vegt E, Veth RP, van der Graaf WT, Schreuder HW. Pigmented villonodular synovitis:

current concepts about diagnosis and management. Future oncology. 2013;9(10):1515-31.

7. Fotiadis E, Papadopoulos A, Svarnas T, Akritopoulos P, Sachinis NP, Chalidis BE. Giant cell tumour of tendon sheath of

the digits. A systematic review. Hand (N Y). 2011;6(3):244-9.

8. van der Heijden L, Gibbons CL, Hassan AB, Kroep JR, Gelderblom H, van Rijswijk CS, et al. A multidisciplinary approach

to giant cell tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal. J Surg

Oncol. 2013;107(4):433-45.

9. Gonzalez Della Valle A, Piccaluga F, Potter HG, Salvati EA, Pusso R. Pigmented villonodular synovitis of the hip: 2- to

23-year followup study. Clin Orthop Relat Res. 2001(388):187-99.

10. Mollon B, Lee A, Busse JW, Griffin AM, Ferguson PC, Wunder JS, et al. The effect of surgical synovectomy and

radiotherapy on the rate of recurrence of pigmented villonodular synovitis of the knee: an individual patient meta-

analysis. Bone Joint J. 2015;97-B(4):550-7.

11. Griffin AM, Ferguson PC, Catton CN, Chung PW, White LM, Wunder JS, et al. Long-term outcome of the treatment

of high-risk tenosynovial giant cell tumor/pigmented villonodular synovitis with radiotherapy and surgery. Cancer.

2012;118(19):4901-9.

12. van der Heijden L, Mastboom MJ, Dijkstra PD, van de Sande MA. Functional outcome and quality of life after the

surgical treatment for diffuse-type giant-cell tumour around the knee: a retrospective analysis of 30 patients. Bone

Joint J. 2014;96-B(8):1111-8.

13. de St. Aubain Somerhausen N, Dal Cin P. Gaint cell tumour of tendon sheath/Diffuse-type giant cell tumour. In:

Fletcher CD, Unni KK, Mertens F, editors. World Health Organization Classification of Tumours Pathology and Genetics

of Tumours of Soft Tissue and Bone. Lyon: IARC Press; 2002. p. 109-14.

14. Myers BW, Masi AT. Pigmented villonodular synovitis and tenosynovitis: a clinical epidemiologic study of 166 cases

and literature review. Medicine (Baltimore). 1980;59(3):223-38.

15. Casparie M, Tiebosch AT, Burger G, Blauwgeers H, van de Pol A, van Krieken JH, et al. Pathology databanking and

biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data

network and archive. Cell Oncol. 2007;29(1):19-24.

16. Verschoor A, Bovee J, van de Sande M, Gelderblom H. Incidence and demographics of giant cell containing tumors

in the Netherlands: a nationwide pathology database study. Annual Meeting of the Connective Tissue Oncology

Society; November 4-7; Salt Lake City, Utah, USA2015.


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217. Rubin DB. Multiple imputation after 18+ years. Journal of the American Statistical Association. 1996;91(434):473-89.



19. Flandry F, Hughston JC, McCann SB, Kurtz DM. Diagnostic features of diffuse pigmented villonodular synovitis of the

knee. Clinical orthopaedics and related research. 1994(298):212-20.

diag

nos

tics

does csF1 over-expression

or rearrangement influence

biological behaviour in

tenosynovial giant cell tumours of the knee?

chap

ter

thre

e

M.J.L. Mastboom1, D.M. Hoek2, J.V.M.G. Bovee3, M.A.J. van de Sande*1, K. Szuhai*2

Histopathology 2018 Aug. doi: 10.1111/his.13744

1 Orthopaedic Surgery, Leiden University Medical Center, Leiden, the Netherlands

2 Cell and Chemical biology, Leiden University Medical Center, Leiden, the Netherlands

3 Pathology, Leiden University Medical Center, Leiden, the Netherlands

*Authors contributed equally to this work.

CSF1 in tenosynovial giant cell tumours

53

3

abstract

Introduction

Localized- and diffuse-type tenosynovial giant cell tumours (TGCT) are regarded different

clinical and radiological TGCT-types. However, genetically and histopathologically they seem

indistinguishable. We aimed to correlate CSF1-expression and CSF1-rearrangement with the

biological behaviour of different TGCT-types with clinical outcome (recurrence).

Methods

Along a continuum of extremes, therapy naïve knee TGCT patients with >3 year follow-up, mean

age 43(range 6-71)years and 56% female were selected. Nine localized-(two recurrences), 16

diffuse-type(nine recurrences) and four synovitis as control were included. Rearrangement of

the CSF1-locus was evaluated with split-apart Fluorescence In Situ Hybridization (FISH) probes.

Regions were selected to score after identifying CSF1-expressing regions, using mRNA ISH with

the help of digital correlative microscopy. CSF1-rearrangement was considered positive in samples

containing >2 split signals/100 nuclei.

Results

Irrespective of TGCT-subtype, all cases showed CSF1-expression and in 76% CSF1-rearrangement

was detected. Quantification of CSF1-expressing cells was not informative, due to the extensive

intra tumour heterogeneity. Of the four synovitis cases, two also showed CSF1-expression, without

CSF1-rearrangement. No correlation between CSF1-expression or rearrangement with clinical

subtype and local recurrence was detected. Both localized- and diffuse-TGCT cases showed a

scattered distribution in the tissue of CSF1-expressing cells.

Conclusion

In diagnosing TGCT, CSF1 mRNA-ISH in combination with CSF1 split-apart FISH; using digital

correlative microscopy, is an auxiliary diagnostic tool to identify rarely occurring neoplastic cells.

This combined approach allowed us to detect CSF1-rearrangement in 76% of the TGCT-cases.

Neither CSF1-expression nor presence of CSF1-rearrangement could be associated with the

difference in biological behaviour of TGCT.

54

Chapter three

introduction

Tenosynovial giant cell tumour (TGCT), previously known as pigmented villonodular synovitis (PVNS)

and giant cell tumour of tendon sheath, is a rare, neoplastic lesion arising from the synovial lining of

joints, bursae or tendon sheaths in predominantly young adults. Excluding digits, this mono-articular

disease is most commonly diagnosed around the knee or other weight bearing joints1-3.

Initially, TGCT was believed to be an inflammatory disease4. After genomic aberrations were

discovered, TGCT was evidently considered neoplastic5-10. Chromosomal aberrations include

trisomy for chromosomes 5 and 7 and translocations involving the short arm of chromosome 1p11-

13, most commonly translocated to chromosome 2q37 region. At the 1p13 breakpoint, Colony

Stimulating Factor 1 (CSF1) gene is located. The translocation leads to a classical promoter fusion

event in which collagen 6A3 (COL6A3) promoter element is fused to CSF1. As a result, the fusion

leads to deregulated expression of CSF111. The excessive CSF1 secretion attracts inflammatory cells

that express the CSF1 receptor (CSF1R) (i.e. monocytes and macrophages). Consequently, in TGCT

tissue, only a small percentage of cells (2-16%) are neoplastic, carrying the t(1;2) translocation.

This phenomenon is coined as “the landscape effect”11, 12. Based on CSF1 rearrangements

(translocation), two groups are described. The first group is defined by both CSF1 over-expression

and CSF1 translocation, whereas the second group lacks the classical translocation. The latter

group likely carries other rearrangements altering CSF1 regulation leading to high CSF1 mRNA

and CSF1 protein levels12.

According to the 2013 WHO classification, TGCT is subdivided in a lobulated well circumscribed

lesion (localized-type) and a more locally aggressive lesion, involving a large part or all of the

synovial lining (diffuse-type)1, 2, 13 (figure 1). Standard choice of treatment was surgical resection of

the lesional tissue, either arthroscopically or with an open resection14-17. The localized-type TGCT is

known with a favourable course after resection (average recurrence rates <6%), while the diffuse-

type TGCT generally causes significant morbidity due to the high risk of local recurrence (>50%

depending on surgical procedure and follow-up time)15, 18, 19. Therefore, at present diffuse-type

TGCT is also treated with CSF1 inhibitors, such as nilotinib, imatinib, pexidartinib, emactuzumab,

cabrilazimab and MSC11020. Long term efficacy data have not yet been reported with these newer

agents.


55

3

Recurrent TGCT is rarely lethal, but a chronic illness with substantial morbidity to the joint leading

to functional and quality of life impairment, caused by the course of the disease itself and multiple

treatments21. Clinically, localized- and diffuse-TGCT are clearly two very different diseases. However,

histopathologically they seem indistinguishable with both subtypes containing an admixture of

mononuclear cells (histiocyte-like and larger cells) and multinucleated giant cells, lipid-laden foamy

macrophages (also known as xanthoma cells), siderophages (macrophages including hemosiderin-

depositions), stroma with lymphocytic infiltrate and some degree of collagenisation1, 2.

It remains unclear why localized- and diffuse-TGCT are microscopically and genetically identical,

but clinically distinct. Moreover, predictors for progressive disease or local recurrence are lacking.

In this study, we investigate whether CSF1 over-expression and rearrangement are correlated

with tumour characteristics (localized-/diffuse-TGCT) and clinical outcome (recurrence). We

hypothesize that diffuse-type TGCT, compared with localized-type TGCT, would have a higher load

of neoplastic cells. We expect that a higher tumour load is associated with recurrent disease.

Figure 1 Localized- and diffuse-TGCT sagittal T1-weighted MR image after intravenous contrast injection with

fat suppression. Tumour region enhances by contrast injection. a. A localized-TGCT involving Hoffa’s fat pad

in the anterior part of the left knee in a 55-year-old female patient (L4835). b. Left knee in a 61-year-old male

patient with extensive recurrent diffuse-TGCT located intra- and extra-articular with an additional posterior

large Baker’s cyst including tumour (L3496).

56

Chapter three

methods

Case acquisition and study design

Subtypes of TGCT (localized- or diffuse) were defined based on clinical features and radiological

imaging according to 2013 WHO1, 2. Along a continuum of extremes, 25 patients with TGCT

affecting the knee were carefully selected: patients with small or very large localized or diffuse

lesions, with and without recurrent disease. All cases showed all characteristic histological features

of TGCT (mononuclear cells, giant cells, macrophages, siderophages, foam cells or lymphocyte-

clusters). Included patients were therapy naïve (one diagnostic arthroscopy elsewhere was

allowed) and treated with open synovectomy at the Leiden University Medical Centre (LUMC).

A clinical follow-up of at least three years was required for inclusion. For comparison, we used

tissue specimens of four patients with non-TGCT synovitis. Written informed consent was

obtained from all patients. This study was performed in accordance with the Code of Conduct

for responsible use in The Netherlands (Dutch Federation of Medical Scientific Societies) and

approved by the local medical ethical committee (P13.029).

Inclusion selected cases and tissue specimens

Nine localized- and 16 diffuse-type TGCT patients were included, mean age at surgery of 43

(range 6-71) years, mean follow-up of 57 (range 36-121) months (table 1), with a slight female

predominance (56%). Two localized- and nine diffuse-type TGCT patients had recurrent disease,

after mean 26 (range 14-53) months. The mean age at surgery of the four patients with non-TGCT

synovitis was 53 (range 44-65) years, including two (50%) females.

For each patient, multiple formalin-fixed paraffin-embedded (FFPE) tissue blocks and

corresponding Haematoxylin and Eosin stained (H&E) 4 μm slides of the primary resected

specimen were reviewed by an expert bone and soft tissue pathologist (JVMGB) to confirm TGCT

diagnosis and to select representative areas of the tumour with highest proportion of suspected

neoplastic cells.

A large tissue heterogeneity was observed between the different blocks. As a control for the

landscaped CSF1 mRNA expression, multiple blocks were selected for three cases (L4046, L3496

and L4954) representing various tissue compositions.


57

3

CSF1 mRNA expression

The RNAscope 2.5 High Definition(HD)-RED assay (Advanced Cell Diagnostics, 322350) was

used to detect CSF1 mRNA expression. This assay visualizes single RNA molecules per cell by a

novel method of in situ hybridization (ISH). The double Z probe design allowed simultaneous

signal amplification and background suppression22. Positive (PPIB (Cyclophilin B)) and negative

controls (bacillus subtilis strain SMY) ensured reliable results. mRNA hybridisation were performed

according to manufacturer’s protocols.

CSF1 rearrangement

To identify the presence of CSF1 rearrangements at region 1p13, DNA Fluorescence In Situ

Hybridisation (FISH) analysis was performed on all tissue specimens using bacterial artificial

chromosome (BAC) clones: RP11-354C7 (centromeric to CSF1) and RP11-96F24 (telomeric to

CSF1)) bracketing CSF1 locus, to identify both translocation and inversion. Probe labelling and

hybridisation were done according to previously described protocols23. An index case outside

of the study population (L4018) was included with a COBRA-FISH molecular karyotyping proven

inv(1)(p13;q23) as reference for the detection of the chromosome inversion in tissue section24.

Detailed description of mRNA ISH and FISH procedures are presented in supplementary material.

Table 1 Descriptives of study population

Localized Localized recurrence Diffuse Diffuse

recurrence No TGCT

Total number 7 2 7 9 4

Mean age at surgery (R), y 33 (6-55) 41 (20-62) 54 (33-71) 42 (17-63) 53 (44-65)

Male:female 5:2 0:2 2:5 4:5 2:2

Mean time to recurrence (R), m na 31 (18;44) na 24 (14-53) na

Mean follow up (R), m 61 (39-100) 81 (40;121) 54 (39-97) 51 (36-70) na

Localized: localized-TGCT; Diffuse: diffuse-TGCT; R: range; y: years; m: months

58

Chapter three

Scoring and correlative analysis

All slides were scanned in brightfield and/or fluorescence on a Pannoramic P250 or MIDI digital scanner

(3DHistech, Budapest, Hungary). Scanned images were visualized using the Pannoramic Viewer (V2.1;

3DHistech). Interpretation was performed manually by a senior FISH expert (KS), blinded towards TGCT-

type and clinical outcome. Because CSF1 expressing regions were expected to contain neoplastic cells,

three of these regions were selected. With the use of digital correlative microscopy, regions with CSF1

mRNA expressing (supposed neoplastic) cells were identified and the same areas were scored after

FISH analysis. If the distance between the two signals was larger than the size of a single hybridization

signal, cells were recorded CSF1 split positive. All nuclei within the selected area with a complete set of

signals were evaluated. Nuclei with an incomplete set of signals were excluded from counting. Samples

containing >2/100 nuclei with a CSF1 split were considered CSF1 split positive.

results

CSF1 mRNA expression

Specimens of all localized- and diffuse-TGCT cases showed a scattered, tissue infiltrating distribution of

CSF1 expressing cells (figure 2). Corresponding to the landscape effect, heterogeneous distribution of

CSF1 expressing cells were observed when sections from multiple bock were analysed, meaning that

regions completely devoid CSF1 expressing cells were seen in regions containing large proportion of

foam cells or regions with lymphocytic infiltrates. CSF1 mRNA pattern expression was not observed in

multinucleate giant cells, siderophages or foam cells. Consequently, due to the great heterogeneity

between different blocks derived from one tumour and within regions in one section, quantification

of CSF1 expressing cells, meaning the expression of the proportion of CSF1 positive cells, was not

informative and was not further analysed (supplementary material figure 1). Selecting the block with

the highest possible neoplastic cell component, we did not observe a clear difference in distribution

of CSF1 between different TGCT cases. Cells with CSF1 mRNA expression were distributed diffusely

and showed an infiltrating scattered pattern throughout the sections with some clustering at various

regions within a tissue element (figure 2, supplementary material figure 2 and 3).

For the control cases, two of the four cases with synovitis showed expression of CSF1 (L5619, L5620).

However, in these two cases CSF1 expression was restricted to cells localised in the synovial lining,

which was different from the scattered distribution seen in TGCT (figure 3). The other two cases with

synovitis showed no expression of CSF1 (L3715, L5622).


59

3

Figure 2 Conventional histology and mRNA ISH from 61-year-old male patient (L3496), with extensive recurrent

diffuse-TGCT. This is the same patient as figure 1 right. Left panel H&E stained section (A; C) with matching CSF1

mRNA ISH (B; D) on the right panel. White box in panel A and B show regions at higher resolution in panel C

and D. Heterogeneous cellular composition of TGCT is visible including foam cells, inflammatory cells, synovial-

like cells, siderophages and characteristic giant cells (A; C). mRNA ISH shows a scattered distribution of CSF1

expressing cells with granular cytoplasmic signals (red signal), identifying CSF1 expressing cell-nuclei (blue

signal after DAPI staining). Green arrowheads shows giant cells without CSF1 expression. Scale bars are in the

right top corner 100µm for panel A and B and 50µm for panel C and D.

a b

c d

60

Chapter three

CSF1 rearrangement

The CSF1 probe set showed a clear split-apart signal even for detection of chromosome inversion

using our molecular karyotyping proven index case with an inv(1)(p13;q23) indicating that cases with

no split signal are unlikely to have similar inversion. Due to great heterogeneity, CSF1 split scoring

was done on selected areas based on presence of CSF1 expressing cells identified by mRNA ISH using

correlative digital microscopy. Using this approach, CSF1-gene rearrangement was detected in 76%

of all TGCT cases: in localized-type 77% and in diffuse-type 75% (figure 4, supplementary material

figure 2). Further stratification of positive cases, rearrangement of the CSF1 locus was present in 78%

of localized-TGCT without recurrence, 100% of localized-TGCT with recurrent disease, 86% of diffuse-

TGCT without recurrence and 67% of diffuse-TGCT including recurrent disease (table 2, supplementary

material table 1 patient and tumour characteristics). There was no CSF1 gene rearrangement in all four

synovitis control cases.

a bFigure 3 Distribution of synovial lining CSF1 mRNA ISH positive cells in TGCT and reactive synovitis.

a. 61-year-old male patient (L3496) with diffuse-type TGCT. Cells with red cytoplasmic staining after mRNA

ISH, show a deep infiltrating pattern in synovial villi with rare occurrence at the synovial lining parts. This is the

same patient as figure 1 right and figure 2. b. 45-year-old female patient (L5620) with synovitis, showing CSF1

expressing cells (red cytoplasmic signal) restricted to cells localised in the synovial lining. Nuclei are displayed

in blue after DAPI staining, scale bars are in the right top corner (100µm).


61

3

Table 2 Proportion of cases with CSF1 mRNA expression and CSF1 gene rearrangement*

N CSF1 over-expression CSF1 gene rearrangement

Localized 7 7 (100%) 5 (78%)

Localized recurrence 2 2 (100%) 2 (100%)

Diffuse 7 7 (100%) 6 (86%)

Diffuse recurrence 9 9 (100%) 6 (67%)

Synovitis 4 2 (50%) 0 (0%)

Localized: Localized-TGCT; Diffuse: Diffuse-TGCT

*Comprehensive patient and tumour characteristics are shown in supplementary material table 1.

Figure 4 Correlative microscopy used to identify neoplastic cells. a. mRNA ISH helps to identify regions

with cells overexpressing CSF1 mRNA (red signal), blue nuclei after DAPI staining. b. CSF1 locus specific split-

apart probe set using BAC probes: centromeric (red) and telomeric (green) probes. Yellow signal represent

co-localization of the signal meaning no rearrangement. White arrowheads indicate cells with split-apart

signal, indicating rearrangement of the CSF1 gene. Samples are from a 61-year-old male patient (L3496), with

extensive recurrent diffuse-TGCT, the same patient as figure 1 A, figure 2, figure 3A. Scale bars are in the right

top corner (20µm)

62

Chapter three

Figure 5 Proposed workflow

for molecular pathology w

ork up of TGC

T cases

Num

bers represent TGC

T cases in this study

CSF1, Colony Stimulating Factor1; m

RNA

ISH, m

RNA

In Situ Hybridization; D

NA

FISH, D

NA

Fluorescence In Situ Hybridisation


63

3

discussion

Localized- and diffuse-type TGCT are histopathologically identical and carry the same chromosomal

translocation, leading to uncontrolled over-expression of CSF1 due to a gene fusion between

COL6A3 and CSF1 genes. Undeniably, localized- and diffuse-type TGCT are clinically different

diseases. In a well-defined TGCT population with >3 years follow-up, molecular differences in

primary resected tissue between both subtypes and clinical outcome (recurrence) were evaluated.

We were unable to find a clear association between CSF1 over-expression or CSF1 rearrangement

and the biological behaviour in TGCT of the knee.

In this study, 76% CSF1 rearrangement was detected when lumping all our 25 cases together,

compared with 61% of the evaluated cases by Cupp et al.12. Further subdivided, our study revealed

no difference in CSF1 rearrangement for localized-TGCT (77%) and diffuse-TGCT (75%). On the

contrary, West et al. reported a large difference between these two types; 87% rearrangement

in localized- and 35% in diffuse-TGCT11. The relatively high percentage of rearrangement in our

study, could be attributed to our scoring on preselected areas, based on high CSF1 expression.

In addition, our DNA FISH analysis, using bacterial artificial chromosome (BAC) clones (RP11-

354C7 and RP11-96F24) bracketing CSF1 locus, identifies not only a translocation, but also an

inversion for CSF1 rearrangements. Panagopoulous et al. revealed a CSF1-S100A10 fusion gene,

with translocation t(1;1)(q21;p11) as the sole karyotypic abnormality25. Nilsson et al. found that

30% of the TGCT specimens did not have a rearrangement involving the 1p13 locus, where CSF1

is located using split-apart interphase FISH approach, similar to ours8. Next to the translocation,

Panagopoulos et al. reported the replacement of the 3’-UTR of CSF1, resulting in over-expression

or a longer lifetime of CSF1 mRNA due to loss of the 3-UTR controlling region25. Similar cryptic

changes leading to loss of smaller gene region involving the 3’-UTR segment of CSF1 are beyond

the detection level of our FISH probes. Next to this, other, yet not identified alterations leading to

deregulated CSF1 expression cannot be ruled out in cases with CSF1 mRNA expression without

CSF1 rearrangement of the CSF1 locus.

Up to date, clinically reliable antibodies working on FFPE tissue sections to detect CSF1 or CSF1R

are lacking. Therefore, mRNA ISH was the best regarded option to identify CSF1 over-expressing

cells. Consistent with previous reports, all 25 evaluated cases showed CSF1 up-regulation11. Exact

64

Chapter three

determination of the proportion of CSF1 expressing cells was considered not meaningful, since in

all tumours considerable intratumoural heterogeneity was observed between selected blocks and

with individual tissue sections, reflecting the “landscape effect”11. This heterogeneity prevents any

conclusion on the true neoplastic cell load in the tumour and a possible correlation to clinical outcome.

Deregulated CSF1 expression is believed to be the central mechanism of tumourigenesis for TGCT.

CSF1, also called macrophage colony-stimulating factor, is a cytokine, produced by many different

cell types including macrophages, fibroblasts, endothelial cells and osteoblasts (and other cancer

types, especially in bone metastasis)26. CSF1 is expressed in neoplastic cells infiltrating throughout

the lesion. Secreted CSF1 recruits non-neoplastic macrophages into the tumour. By binding to

its receptor CSF1R (type III receptor tyrosine kinase), CSF1 promotes survival, proliferation and

differentiation of cells of the mononuclear phagocyte lineage (e.g. monocytes, macrophages and

osteoclasts)27, 28. Besides its general biological function, CSF1 is also involved in inflammatory or

reactive synovitis (rheumatoid arthritis, chronic artritis) and cancer (breast, endometrial, ovarian,

lung, kidney)12, 27. When CSF1 is expressed in reactive synovitis, its expression is restricted to cells in

the synovial lining12, 29, as was confirmed in our synovitis control cases.

Inhibition of signalling between CSF1 and CSF1R targets the underlying cause of the disease29,

30. The involvement of this pathway contributed to the introduction of systemic therapies for

extensive diffuse-TGCT20. Primarily, imatinib31 or related drugs as nilotinib32 showed efficacy

in the treatment. Recently, new CSF1R blockers were developed and are investigated in clinical

trials; Emactuzumab and Cabiralizumab (FPA008) both monoclonal antibodies directed against

CSF1R33-35; Pexidartinib (PLX3397; retains CSF1R in inactive state)29, and MSC110 (an antagonist of

the CSF1 ligand)35. Emactuzumab (N=29) showed an overall response rate of 86% (two patients

with a complete response) and a rate of disease control of 96%, including a significant functional

and symptomatic improvement (median follow up 12 months)33. The preliminary results for

cabiralizumab (N=22) are consistent, with radiographic response and improvement in pain and

function in five out of 11 patients (45%)34. In a randomized, placebo-controlled phase 3 study,

pexidartinib showed an improved overall response rate by RECIST: 39% in the pexidartinib-group

(N=61) and 0% of placebo-group (N=59), after median six months follow-up36. However, long term

results still need to be evaluated with these newer agents.


65

3

Within our well-defined patient cohort, all patients had a minimum follow-up of three years.

However, patients without recurrent disease at the time of analysis could still develop this in due

course, since it is known that local recurrence might develop years after initial surgery1, 2, 15, 19, 37.

Verspoor et al. calculated an overall recurrence rate of 72% in 75 patients with diffuse-TGCT of the

knee with a mean follow-up from index treatment of 13.9 years. They suggested a trend towards

the longer the follow-up, the greater the number of recurrences19.

In conclusion, DNA FISH analysis, using bacterial artificial chromosome (BAC) clones (RP11-354C7

and RP11-96F24) bracketing CSF1 locus, can identify both chromosomal rearrangement caused

translocation or inversion of the CSF1 locus. Figure 5 summarizes the workflow in the current

study and the proposed workflow for molecular pathology work up of TGCT cases. The use of CSF1

mRNA ISH in combination with CSF1 split-apart FISH is an auxiliary diagnostic tool to confirm the

diagnosis of TGCT. This combined approach allowed us to detect CSF1-gene rearrangement in 76%

of the TGCT cases. At the molecular level, localized- and diffuse-type TGCT are indistinguishable

when evaluating CSF1 expression and the presence of the pathognomonic translocation involving

the CSF1 gene.

Supplementary data

Supplementary data are available in the online version of this article, doi: 10.1111/his.13744

66

Chapter three

Supplementary figure 1 Low power magnification overview of TGCT case from a 61-year-old male patient

(L3496), the same patient as figure 1 A, figure 2, figure 3A, figure 4. a. Hematoxyllin-eosin staining. b. CSF1

mRNA ISH (red) of the same case depicting identical regions, nuclei are stained with DAPI (blue). White

arrowheads indicate blood vessels with erythrocytes, giving a strong red fluorescing signal. A heterogeneous

distribution of CSF1 expressing cells with remarkable variation in their distribution in the tissue is clearly visible.

White squared inset, indicates regions in high power magnification shown in details in figure 2. Scale bars are

in the right top corner (500 µm).

Supplementary figure 2 (right page) Overview of TGCT localized case without

recurrence from a 55-year-old female patient (L4385), presented in figure 1A. a

& b. Hematoxillin-eosin staining low and high power overview. b & d. CSF1 mRNA

ISH (red) of the same case depicting identical regions, nuclei are stained with DAPI

(blue). In panel B a white squared inset indicate the region shown in high power

magnification in panel D. e. Using correlative microscope areas with more neoplastic

cells (mRNA ISH positive cells) were identified and scored for CSF1 locus specific

split-apart probe set using BAC probes. Yellow signal represent co-localization

of the signal meaning no rearrangement. White arrowheads indicate cells with

split-apart signal, indicating rearrangement of the CSF1 gene. Scale bars are at the

bottom left corners and 500 and 20 µm for low and high power images, respectively.

a b


67

3

a b

c d

e

68

Chapter three

Supplementary figure 3 Correlative microscope image comparing sections after hematoxillin-eosin staining

(a) and CSF1 mRNA ISH (b) of a diffuse, non-recurrent TGCT case from a 50-year-old male patient (L3697).

Diffuse infiltrating CSF1 expressing cells are present throughout the section. Scale bars are at the left bottom

corner (200 µm).

a

b


69

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sev

erit

yseverity

classification of tenosynovial

giant cell tumours on mr imaging

chap

ter

four

M.J.L. Mastboom*1, F.G.M. Verspoor*2, D.F. Hanff3, M.G.J. Gademan4, P.D.S. Dijkstra1, H.W.B. Schreuder2, J.L. Bloem3,

R.J.P. van der Wal1, M.A.J. van de Sande1

Surgical oncology. 2018 Sept;27(3):544-550



3 Radiology, Leiden University Medical Centre, Leiden, the Netherlands

4 Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands


Severity classification of tenosynovial giant cell tumours

75

4

abstract

Aim

Current development of novel systemic agents requires identification and monitoring of extensive

Tenosynovial Giant Cell Tumours (TGCT). This study defines TGCT extension on MR imaging to

classify severity.

Methods

In part one, six MR parameters were defined by field-experts to assess disease extension on MR

images: type of TGCT, articular involvement, cartilage-covered bone invasion, and involvement of

muscular/tendinous tissue, ligaments or neurovascular structures. Inter- and intra-rater agreement

were calculated using 118 TGCT MR scans. In part two, the previously defined MR parameters were

evaluated in 174 consecutive, not previously used, MR-scans. TGCT severity classification was

established based on highest to lowest Hazard Ratios (HR) on first recurrence.

Results

In part one, all MR parameters showed good inter- and intra-rater agreement (Kappa≥0.66). In

part two, cartilage-covered bone invasion and neurovascular involvement were rarely appreciated

(<13%) and therefore excluded for additional analyses. Univariate analyses for recurrent disease

yielded positive associations for type of TGCT HR12.84(95%CI4.60-35.81), articular involvement

HR6.00(95%CI2.14-16.80), muscular/tendinous tissue involvement HR3.50(95%CI1.75-7.01) and

ligament-involvement HR4.59(95%CI2.23-9.46). With these, a TGCT severity classification was

constructed with four distinct severity-stages. Recurrence free survival at 4 years (log rank p<0.0001)

was 94% in mild localized (n56, 1 recurrence), 88% in severe localized (n31, 3 recurrences), 59% in

moderate diffuse (n32, 12 recurrences) and 36% in severe diffuse (n55, 33 recurrences).

Conclusion

The proposed TGCT severity classification informs physicians and patients on disease extent and

risk for recurrence after surgical treatment. Definition of the most severe subgroup attributes to a

universal identification of eligible patients for systemic therapy or trials for novel agents.

76

Chapter four

introduction

Tenosynovial Giant Cell Tumour (TGCT) affecting large joints is an orphan, mono-articular,

potentially locally aggressive disease with high recurrence rates. According to the 2013 WHO

classification of tumours of soft tissue and bone, at the base of growth pattern, a radiological

distinction is made between single nodule (localized-TGCT) and multiple lesions (diffuse-TGCT).

These types differ in their clinical presentation, response to treatment and prognosis, but

histologically, they seem identical1-4.

Localized-type TGCT is classified as a circumscribed benign small (between 0.5 and 4 cm) mass1,

5. Standard treatment of choice is excision. Subsequently, overall reported recurrence rates are

relatively low: 0-6%6. On the contrary, diffuse-type TGCT, previously named Pigmented VilloNodular

Synovitis (PVNS), extensively involves the synovial membrane and infiltrates adjacent structures6,

7. Reported recurrence rates of diffuse-TGCT following open synovectomy are 14% up till 67% and

after arthroscopic synovectomy 40% up till 92%6. Recurrent or residual disease, frequently requiring

multiple, sometimes mutilating operations, may result in total joint arthroplasties, morbidity and

loss of quality of life8-12. With this large variety in disease presentation and recurrence rates, a

more comprehensive and outcome-based classification is asked for. The emerging era of systemic

targeted and multimodality therapies (available in trial settings) increases the need for a method

to select eligible patients in order to create comparable patient cohorts13-15.

In diagnosing and treating TGCT, magnetic resonance (MR) imaging is the most distinctive imaging

technique4, 16-19. MR imaging reveals conspicuous nodular (localized-type) or villous proliferation of

synovium (diffuse-type). However, current literature lacks specific MR discriminating features to

describe or quantify tumour extent in relation to clinical outcome. Uniform MR descriptions are

of utmost importance for clinical and research purposes. Therefore this study aims to sub-classify

tumour severity especially in diffuse-type TGCT. First, a group of radiologists and orthopaedic

surgeons identified and defined potentially distinguishing parameters. Second, these MR

parameters were applied on a different study-population to establish TGCT severity subgroups.


77

4

methods

Part I: Identification and evaluation of TGCT specific MR parameters

Using case discussions in expert meetings with two dedicated musculoskeletal radiologists and

three oncological orthopaedic surgeons, six MR parameters were selected in relation to anatomical

or surgical landmarks. These parameters were 1 type of TGCT (based on 2013 WHO classification1, 2),

2 articular involvement, 3 cartilage-covered bone invasion, 4 involvement of muscular/tendinous

tissue, 5 involvement of ligaments and 6 involvement of neurovascular structures (figure 1)

(Appendix).

To evaluate usability and reproducibility, 118 MR scans of TGCT patients, treated at the Leiden

University Medical Centre (LUMC), were randomly retrieved (MM). The six MR parameters were

evaluated in a heterogeneous group of TGCT cases as scans included cases of various large

joints (knee (79; 67%), ankle (13; 11%), foot (10; 9%)), severity subtypes and treatment phases.

MR scans were conducted using a 1.5 or 3.0 Tesla unit Philips (Best, The Netherlands) Ingenia MR

with dedicated coils. Standard musculoskeletal scan-protocol included: T1- and T2-weighted fast

spin echo, T1-weighted fat-suppressed post Gd-chelate contrast and optionally T2* gradient-

echo sequences in two planes (transversal and either sagittal or coronal). To assess inter- and

intra-rater agreement, all MR scans were evaluated by one dedicated musculoskeletal radiologist

(DH) and by two dedicated orthopaedic surgeons (RW, MS). MR evaluation was blinded to patient

characteristics.

Inter-rater agreement and accompanying 95% confidence interval (95% CI) between three

physicians was calculated for all 118 cases by Fleiss-Kappa (dichotomous outcomes in all parameters,

except for articular involvement with three outcomes). To evaluate intra-rater agreement with the

accompanying 95% CI (linear weighted kappa), 36 randomly chosen MR scans (31%) were again

evaluated three months after initial evaluation by the senior orthopaedic surgeon (MS).

Part II: Application of TGCT MR parameter

None of the MR scans in part I were used in part II. The combined TGCT-database of two sarcoma

centres in The Netherlands (LUMC and Radboud University Medical Centre (RUMC)) was used to

include consecutive MR scans conducted between 2005 and 2015 (n=283). MR scan inclusion

criteria were: pre-treatment MR scan of histologically proven TGCT of large joints, conducted in

two planes (transversal and either sagittal or coronal), and open resection as primary treatment

78

Chapter four

Figure 1 Definition of six TGCT specific MR parameters

TGCT-type

a. Localized-type on a sagittal PD-weighted FSE MR image of a 49 year old female patient. Localized-TGCT

is defined according to WHO as a well circumscribed nodular lesion at synovial lining of bursa, joint or

tendon sheath.

b. Diffuse-type on a sagittal PD-weighted FSE MR image of a 24 year old male patient. Diffuse-TGCT is

defined as a multinodular lesion involving a larger part or multiple compartments of the synovial lining.

Articular involvement

c. Intra-articular well circumscribed lesion on posterior cruciate ligament on a PD-weighted FSE MR

image of a 18 year old female patient. Intra-articular involvement is defined as TGCT involvement inside

synovial lining of joint.

d. Extra-articular involvement, along gastrocnemius muscle insertion, on a sagittal T1-weighted FSE MR

image of a 33 year old male patient. Extra-articular involvement is defined as TGCT involvement outside

synovial lining of the joint.

e. Both intra- and extra-articular involvement on a sagittal T1-weighted fat-suppressed MR image after

intravenous administration of gadolinium of a 63 year old female patient with TGCT. Extensive tumour

growth anterior and posterior.

Cartilage-covered bone invasion

f. Cartilage covered bone invasion on a sagittal T1-weighted FSE MR image of a 59 year old male patient.

Square presents cartilage covered bone, defined as clear invasion of bone through cartilage; not only

touch cartilage. Circle presents not-cartilage covered bone invasion.

Muscular/tendinous tissue involvement

g. Muscular/tendinous tissue involvement, anterior vastus medialis muscle and posterior hamstrings

tendon, on a sagittal T1-weighted fat-suppressed MR image after intravenous administration of

gadolinium of a 63 year old female patient with TGCT. Muscular/tendinous tissue is defined as

involvement of muscular/tendinous tissue or >180 degrees encagement of tendon/muscle.

Ligament involvement

h. Cruciate ligament enhancement on a sagittal T1-weighted fat-suppressed MR image after intravenous

administration of gadolinium of a 64 year old male patient. Ligament involvement is defined as

involvement of ligament or >180 degrees encagement of ligament.

Neurovascular structures involvement

i. Popliteal artery encagement on an axial PD-weighted FSE MR image of a 62 year old female patient,

referred to a tertiary sarcoma centre with extensive TGCT. Neurovascular involvement is defined as >

180 degrees encagement of the artery or nerve.

FSE, Fast Spin Echo; PD, Proton Density

Figure e & g is the same female patient.


79

4

a b c

d e f

g h i

80

Chapter four

in one of the two participating centres. Large joints were defined as all joints proximal to and

excluding metatarsophalangeal and metacarpophalangeal joints. When TGCT affected the knee,

one diagnostic arthroscopy prior to open resection was allowed, since tumour extent would not

be affected. Open synovectomy was defined as gross total resection of disease, either one- or two-

staged, without adjuvant therapy. 174/283 Patients met the inclusion criteria (figure 2). Median

follow-up was 36 (IQR 21-60) months, maximum follow-up 12 years after primary surgery.

The senior author (MS) evaluated the six defined MR parameters (part I) on these pre-treatment

scans (77 LUMC, 97 RUMC). MR evaluation was blinded to patient characteristics and clinical

outcome. Patient and tumour characteristics were gathered: gender, localization (affected joint),

age at time of the MR scan, date of open synovectomy, first local recurrence and date of first

recurrence (on MR imaging), and date of last follow-up. Median follow-up was calculated from date

of primary surgery to date of last clinical follow-up, including interquartile range (IQR). Recurrence

free survival was calculated from date of surgery to recurrent disease or last contact.

As outcome, first recurrence was defined as new disease presence after synovectomy or growing

residual disease (diagnosed on follow-up MR scan). Proposed risk factors were gender, localization

(knee versus other joints) and age at the time of the MR scan (below or above 40 years). Hazard

ratios (HRs) and their corresponding 95% CI were estimated for risk factors and MR parameters

Figure 2 Inclusion flowchart part II TGCT severity classification.

283 consecutive TGCT MR scans

Excluded60 not therapy naïve

39 not primarily treated with open synovectomy10 no pre-treatment MR scan available

174 included MR scans


81

4

(part I) by univariate and multivariate Cox regression analyses to estimate the relation on recurrent

disease. Since estimating HR is unreliable for rarely present MR parameters, only parameters with

an adequate number of presence (minimum of 20%) were used for additional analyses. Recurrence

free survival close to median time of follow-up was calculated by Kaplan Meier analyses and log

rank test. Time zero was defined as date of primary open synovectomy.

At the base of HRs with positive associations of risk factors and MR parameters on first recurrences,

the TGCT severity classification was established. The TGCT subgroup flow chart started with the

MR parameter with highest HR, followed by descending HRs. Statistical Package for Social Statistics

(SPSS) version 23 was used for analyses.

Ethical statement

This study was approved by the institutional review board from our institution (registration

number P13.029). No funding was received.

results

Part I: Evaluation of TGCT specific MR parameters

Inter-rater agreements for type of TGCT, articular involvement, cartilage-covered bone invasion,

and involvement of muscular/tendinous tissue, ligaments or neurovascular structures were 0.71;

0.68; 0.66; 0.67; 0.75 and 0.73, respectively. Intra-rater agreements for these parameters were

between 0.72 and 1.00 (table 1). Since inter- and intra-rater agreements were good20 for these six

MR features, all parameters were considered viable to use for TGCT subgroup analyses.

Part II: Application of TGCT MR parameters

Out of 174 MR scans, the knee was affected most (122; 70%), followed by the ankle (20; 12%)

(table 2). In univariate analyses, none of the proposed risk factors were associated with recurrent

disease (p>0.37) (table 3) and consequently not used for further analyses. Both MR parameters

cartilage-covered bone invasion and involvement of neurovascular structures were rarely seen on

MR images (< 13%) and in accordance with our exclusion criteria not used for additional analyses.

In univariate analyses, the remaining four MR parameters were associated with recurrent disease

(p<0.002) (table 3); strongest association was seen in diffuse-type compared with localized-type

82

Chapter four

Table 1 Inter- and intra-rater agreement (kappa) in six M

R parameters

Agreem

entType of TG

CTA

rticular involvem

entCartilage-covered

bone invasion

Muscular/

tendinous tissue involvem

ent

Ligament

involvement

Neurovascular

involvement

Inter-rater0.71 (0.60-0.81)

0.68 (0.58-0.78)0.66 (0.56-0.76)

0.67 (0.56-0.77)0.75 (0.57-0.93)

0.73 (0.62-0.83)

Intra-rater0.94 (0.82-1.06)

0.89 (0.74-1.04)0.79 (0.39-1.19)

0.72 (0.50-0.94)0.86 (0.68-1.04)

1.00 (1.00-1.00)

Inter-rater, Agreement betw

een three physicians (one musculoskeletal radiologist, tw

o orthopaedic surgeons).

Intra-rater, Agreement for 31%

of MR scans initially evaluated and re-evaluated 3 m

onths thereafter by the senior orthopaedic surgeon.

Interpretation of inter- and intra-rater agreement (K-value) 20

Agreem

ent value Strength of agreem

ent

< 0.20

Poor

0.21 - 0.40 Fair

0.41 - 0.60 M

oderate

0.61 - 0.80 G

ood

0.81 - 1.00 Very good


83

4

(HR 12.84 (95%CI 4.60-35.81)), subsequently intra- and extra-articular involvement compared

with extra-articular (HR 6.00 (95%CI 2.14-16.80)) and involvement of muscular/tendinous tissue or

ligaments compared with no involvement (HR 3.50 (95%CI 1.75-7.01), HR 4.59 (95%CI 2.23-9.46),

respectively).

Multivariate analyses for MR parameters did not show individual positive association, except for

parameter type of TGCT (supplementary material I).

Four TGCT severity subtypes were established using a flowchart that begins with the parameters

with highest HR (parameter type of TGCT), followed by parameters with descending HRs. These

four subtypes showed a clinically relevant or significant prognostic value for recurrent disease

and were classified as: mild localized (n56, 1 recurrence), severe localized (n31, 3 recurrences),

moderate diffuse (n32, 12 recurrences) and severe diffuse (n55, 33 recurrences).

1. Mild localized contained localized-type, either intra- or extra-articular involvement

without involvement of muscular/tendinous tissue/ligaments.

2. Severe localized included localized-type, either intra- or extra-articular lesions and

either or both involvement of muscular/tendinous tissue/ligaments.

3. Moderate diffuse comprised diffuse-type with intra- and/or extra-articular disease


4. Severe diffuse was diffuse-type including intra- and extra-articular involvement

and involvement of at least one of the three structures (muscular/tendinous tissue/

ligaments) (figure 3).

Recurrence free survival at 4 years (close to median follow-up diffuse-type) for the four patient

groups according to the new MR subtypes descended from 94% in mild localized, to 88% in severe

localized, to 59% in moderate diffuse and to 36% in the least favorable subtype, severe diffuse.

Median time to local recurrence in moderate diffuse and severe diffuse subtypes was 29.5 (IQR

14.5-48.0) and 22.0 (IQR 11.8-33.5) months, respectively. Majority of recurrent disease cases were

already treated with a re-operation (32/49, 65%). One patient, classified as severe diffuse, died of

another disease, after four months and was censored at that time. Novel MR based TGCT severity

and associated Kaplan Meier survival curves presented significant difference between the four

patient groups (log rank p<0.0001) and additional differentiation compared with solely sub-

classifying in localized- and diffuse-TGCT (figure 4 and supplementary material II).

84

Chapter four

Table 2 TGCT MR scan demographics

Cases (%) Cases localizedTGCT (%)

Cases diffuseTGCT (%)

Total number of MR scans 174 87 87

Gender

Female 105 (60) 33 (38) 36 (41)

Male 69 (40) 54 (62) 51 (59)

Median age at MR scan (IQR) 37 (26-48) years 37 (24-47) years 36 (26-49) years

Localization

Knee 122 (70) 63 (72) 59 (68)

Hip 8 (5) 0 (0) 8 (9)

Ankle 20 (12) 10 (11) 10 (11)

Foot 9 (5) 5 (6) 4 (5)

Elbow 6 (3) 4 (5) 2 (2)

Other 9 (5) 5 (6) 4 (5)

Median follow-up (IQR) 36 (21-60) months 32 (17-56) months 41 (24-63) months

Total number of recurrences

Recurrent disease 49 (28) 4 (5) 45 (52)

No recurrent disease 125 (72) 83 (95) 42 (48)

IQR, interquartile range


85

4

Table 3 Risk of recurrence on MR imaging;

univariate analyses in proposed risk factors and four MR parameters.

n (%) Hazard ratio (95% CI) P

Gender

Male 69 (40) 1.29 (0.74-2.27) 0.37

Female 105 (60) 1

Age

<40 years 91 (52) 1.15 (0.66-2.02) 0.63

>40 years 83 (48) 1

Localization

Knee 122 (70) 1.15 (0.63-2.12) 0.65

Other joint 52 (30) 1

TGCT-type

Diffuse 87 (50) 12.84 (4.60-35.81) <0.000

Localized 87 (50) 1

Articular involvement

Intra-articular 59 (34) 1.11 (0.31-3.95) 0.87

Intra- and extra-articular 75 (43) 6.00 (2.14-16.80) 0.001

Extra-articular 40 (23) 1

Muscular/tendinous tissue involvement

Yes 90 (52) 3.50 (1.75-7.01) <0.000

No 84 (48) 1

Ligament involvement

Yes 86 (49) 4.59 (2.23-9.46) <0.000

No 88 (51) 1

86

Chapter four

Figure 3 TGCT severity classification, containing four severity subtypes: mild localized, severe localized,

moderate diffuse and severe diffuse.

no ≥1

mild localizedRFS 4y: 94%

severe localizedRFS 4y: 88%

type of TGCT

articular involvement

involvement of ligaments/muscular/

tendinous tissue

TGCT severity stage

localized


87

4

RFS 4y, Recurrence Free Survival at 4 years

diffuse

intra or extra intra and extra

no ≥1

moderate diffuseRFS 4y: 59%

severe diffuseRFS 4y: 36%

88

Chapter four

Time (years) 0 2 4 6 8

Number at risk 174 105 51 24 10

Figure 4 TGCT recurrence free survival curve for four TGCT severity subtypes, affecting large joints, estimated

with Kaplan Meier method. Time zero was date of primary open synovectomy. One patient, classified as severe

diffuse died of another disease after 4 months and was censored at that time.

Follow-up time (years)

Cum

ulat

ive

recu

rren

t TG

CT

severe diffuse

moderate diffuse

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8

0.0

mild localized

severe localized


89

4

discussion

This is the first study to define severity subtypes in Tenosynovial Giant Cell Tumours (TGCT) based

on a combination of four MR imaging parameters. These subtypes correlate with a spectrum of

disease severity ranging from low to high risk of local recurrence after surgical intervention.

Within this present era of systemic targeted and multimodality therapies (available in trial settings)

in TGCT, standalone surgical resection cannot be regarded the gold standard anymore for more

severe cases21. Because of the lack of clear-cut boundaries in diffuse-TGCT, complete resection is

difficult and at times technically impossible or undesirable with joint function preservation and

quality of life in mind. In patients with locally advanced TGCT or (multiple) recurrence(s), systemic

therapies targeting the CSF1/CSF1R axis have been investigated; less potent drugs as nilotinib and

imatinib22, 23, and more specific inhibitors as emactuzumab (RG7155), pexidartinib (PLX3397) and

cabiralizumab (FPA008). Emactuzumab (N=29) had an overall response rate of 86% (two patients


and symptomatic improvement (median follow up 12 months)24. In a randomized, placebo-

controlled phase 3 study, pexidartinib showed an improved overall response rate by RECIST:

39% in the pexidartinib-group (N=61) and 0% of placebo-group (N=59), after median six months

follow-up25. The preliminary results with cabiralizumab (N=22) are consistent, with radiographic

response and improvement in pain and function in five out of 11 patients 2815. However, long term

efficacy data have not yet been reported with these newer agents.

Patient inclusion for these trials is very heterogeneous. A strict patient selection is desirable, to

accurately evaluate effect of these treatments. At present, patient selection for trial inclusion

is established by preference of treating physician and might differ per centre. Defining more

aggressive TGCT subtypes and including these uniformly defined patients into trials would more

adequately investigate the effect and toxicities of treatment26. In this study, we propose to include

patients defined with ‘severe diffuse’ TGCT subtype. Monitoring the effect of systemic therapy also

benefits from clear agreements on parameters.

Uniform MR descriptions are of utmost importance for clinical and research purposes. Thus far,

no well-defined tumour parameters exist. Definition of unambiguous MR criteria is challenging,

90

Chapter four

because of the rarity of the tumour and small number of heterogeneous cases, variety of joints

involved, different disease severity as well as several treatment modalities2, 27. So far, MR imaging

has shown to be the best discriminating method to evaluate TGCT4, 28. In our study, six objective

clinically relevant MR parameters were defined in relation to anatomical or surgical landmarks.

According to our exclusion criteria for the development of the severity classification, parameters

cartilage covered bone invasion and neurovascular involvement showed inadequate number of

presence and were therefore not used. However, in larger case series these two parameters might

correlate with more aggressive disease and hence a higher recurrence rate.

To date, no radiology-based TGCT severity classification exists. Subdividing between localized-

and diffuse-TGCT seems an oversimplification that fails to estimate differences in recurrent rates

for individual patients. Murphey et al. presented an extensive review of different TGCT features

on several imaging techniques, without relating these features to disease severity, treatment or

recurrences4. Van der Heijden et al. further sub-classified diffuse-TGCT affecting the knee in 30

patients into mild or severe, without linking to recurrent disease. Mild diffuse-TGCT was defined as

involvement of either anterior or posterior compartment of the knee, with the cruciate ligaments

as boundary. Severe diffuse-TGCT was defined as involvement of both compartments, with or

without extra-articular extension9. In contrast to most literature, we selected a homogeneously

treated patient population to develop four severity subtypes, by only including patients initially

treated with an open synovectomy.

In line with most papers, especially papers on trial medication, and based on clinical practice,

we included all large joints to sub-classify disease severity for TGCT. Prior research did not

show a (significant) difference in recurrence rates for both localized and diffuse disease when

comparing the knee with other joints6, 27, 29, 30. A recent TGCT incidence calculation study showed

a predominance of the knee in 46% in localized- and 64% in diffuse-type (excluding digits)5, in

line with our overrepresentation of the knee of 70%. In the future, a TGCT severity classification

focused on the knee would contain more detailed knee-specific MR parameters and equal

treatment approaches.

Limitations to this study: primary, the resulting HRs had wide confidence intervals, indicating low


91

4

precision in the estimates. This is likely related to the relatively small sample size, given that the

patients were divided into several groups based on the MR parameters. Secondly, because of the

relatively small number of recurrences in severity subtypes mild localized (n 1) and severe localized

(n 3), Hazard Ratios may be unreliable. Therefore, it was not feasible to estimate a cox model and to

generate a true prediction model. Additionally, localized-TGCT is known to have few recurrences

and often remains without clinical complaints after resection. In both sarcoma centres, patients

are therefore discharged from follow-up after the first follow-up post-surgery and requested to

return again when clinical complaints present. In our analyses, 31 localized-type patients were

censored at date of last clinical follow-up within the first two years in survival curve (figure 4). Less

often, patients with diffuse-type have also lacked follow-up (13 censored first two years). It could

be assumed that these patients did not have complaints and recurrent disease. Furthermore, in

study part two (establishing TGCT subtypes), newest included MR scans originated from 2015.

These cases had a maximum follow-up of two years. Since it is known that local recurrence might

develop years after initial surgery2, 11, 29, in our study a median of 29.5 in moderate diffuse and

22.0 months in severe diffuse-TGCT subtypes, underestimation of recurrence free survival could be

present. Finally, even though quite a large number of MR scans (174) were used in development of

the severity classification, in larger case-series including long follow-up time, it might be possible

to differentiate further in disease severity and assess additional subtypes.

To conclude, in reporting TGCT affecting large joints on MR imaging, six parameters are helpful

in discriminating disease extent. Patients can be accurately monitored by using these MR

parameters. With respect to recurrence, a combination of four MR parameters classifies patients

into one of four severity subtypes, presented with distinct recurrence free survival rates. In the era

of personalized medicine, treatment is individualized for each patient depending on the extent of

disease. Because histopathological prognostic factors are lacking, sub-classification of TGCT on MR

imaging is a potential tool to stratify future patient prognosis and identify candidates for targeted

therapies, thereby aiding with the decision in daily practice.

Supplementary data

Supplementary data related to this article can be found at

https://doi.org/10.1016/j.suronc.2018.07.002

92

Chapter four

appendix

TGCT MR parameters, affecting large joints, in therapy naïve primary TGCT patients

Agreement:

Involvement of a structure: when signal intensity is changed to TGCT signal intensity,

this structure is considered to be involved with TGCT and to be scored.

When involvement of a structure is unclear: choose ‘structure involved’ (when in

doubt; over-scoring, not under-scoring).

MI parameters

1. TGCT-type

Localized-type†: well circumscribed nodular lesion at synovial lining of bursa,

joint or tendon sheath

Diffuse-type††: multinodular lesion involving a larger part or all of the synovial

lining

2. Articular involvement

Intra-articular$: inside synovial lining of joint

Extra-articular$$: outside synovial lining of joint

Both intra- and extra-articular

3. Cartilage-covered bone invasion

Yes: clear invasion of bone invading cartilage; not only touch cartilage

No: no bone invasion or solely bone-usuration or bone invasion not cartilage-

covered

4. Muscular/tendinous tissue involvement*

Yes: involvement of muscular/tendinous tissue or >180 degrees encasement

of tendon/muscle

No: no involvement or encasement of tendon/muscle

5. Ligament involvement**

Yes: involvement of ligament or >180 degrees encasement of ligament

No: no involvement or encasement of ligament


93

4

6. Neurovascular structure involvement#

Yes: encasement >180 degrees of important nerves and/or vessels

No: no encasement of nerves or vessels

† Localized-type: be careful to always classify one nodular lesion as localized-type. Also when one

nodular lesion is reeved by another structure (it might seem like additional nodules).†† Diffuse-type: be careful to always classify diffuse-type when two or more tendon sheaths or

muscles are involved. Do not classify these cases as one large nodule.$ Intra-articular: concerning the knee: cruciate ligaments are counted as intra-articular structures

as the synovial lining of the ligaments should be considered intra-articular.$$ Extra-articular: concerning the knee: Hoffa

* Muscular/tendinous tissue involvement: concerning the knee: also account parameter when

solely popliteus muscle involvement is present.

** Ligament involvement: TGCT involvement of ligament, in hand or foot: account parameter

when intra-tarsal/digital ligaments, ankle syndesmose and plantar fascia are involved. TGCT

concerning the knee with ligament involvement: anterior and/or posterior cruciate ligament,

and/or medial/lateral collateral ligament.# Neurovascular involvement: in hand or foot: also digital or sensible nerves

94

Chapter four

references





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2013;107(4):433-45.

7. Tyler WK, Vidal AF, Williams RJ, Healey JH. Pigmented villonodular synovitis. The Journal of the American Academy of

Orthopaedic Surgeons. 2006;14(6):376-85.





2014;96-B(8):1111-8.

10. Verspoor FG, Hannink G, Scholte A, Van Der Geest IC, Schreuder HW. Arthroplasty for tenosynovial giant cell tumors. Acta

orthopaedica. 2016;87(5):497-503.





2012;118(19):4901-9.

13. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure-Guided Blockade of CSF1R Kinase in

Tenosynovial Giant-Cell Tumor. The New England journal of medicine. 2015;373(5):428-37.

14. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-

1R antibody reveals a strategy for cancer therapy. Cancer cell. 2014;25(6):846-59.





radiology. 1995;24(1):7-12.




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20. Altman D. Practical Statistics for Medical Research. Hall/CRC Ca, editor 1990.

21. Staals EL, Ferrari S, Donati DM, Palmerini E. Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and

future perspectives. Eur J Cancer. 2016;63:34-40.



Cancer. 2012;118(6):1649-55.






25. Tap WD GH, Stacchiotti S, Palmerini P, Ferrari S, Desai J, Bauer S, Blay JY, Alcindor T, Ganjoo KN, Martin Broto J, Ryan CW,

Edward Shuster DE, Zhang L, Wang Q, Hsu H, Lin PS, Tong S, Wagner AJ, editor Final results of ENLIVEN: A global, double-

blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT).

ASCO conference; 2018; Chicago.

26. Gounder MM, Thomas DM, Tap WD. Locally Aggressive Connective Tissue Tumors. Journal of clinical oncology : official

journal of the American Society of Clinical Oncology. 2018;36(2):202-9.

27. Chiari C, Pirich C, Brannath W, Kotz R, Trieb K. What affects the recurrence and clinical outcome of pigmented villonodular

synovitis? Clin Orthop Relat Res. 2006;450:172-8.

28. Gouin F, Noailles T. Localized and diffuse forms of tenosynovial giant cell tumor (formerly giant cell tumor of the tendon

sheath and pigmented villonodular synovitis). Orthop Traumatol Surg Res. 2017;103(1S):S91-S7.






Ho

rm

on

escan increased

symptoms of tenosynovial giant

cell tumours during pregnancy be explained by a change in female

sex hormones?

chap

ter

five

M.J.L. Mastboom1, F.G.M. Verspoor2, R. Planje1, H.W.B. Schreuder2, M.A.J. van de Sande1

Submitted.

98

Chapter five



Female sex hormones in TGCT

99

5

abstract

Objective

Tenosynovial Giant Cell Tumours (TGCT), both localized- and diffuse-type, are rare, mono-articular

neoplasms, with a slight female predominance. The clinical behaviour between patients differs

greatly. This study aims to evaluate the increase in TGCT-related symptoms during pregnancy and

the influence of female sex hormones thereon.

Methods

In a prospective-cohort-study, TGCT-related symptoms before and during pregnancy were

evaluated in two Dutch centres and by use of the largest online TGCT patient-support group.

Second, as a proxy for disease activity the combined TGCT-database of two sarcoma-centres

in the Netherlands (N=455) was used to compare recurrence free survival rates between the

sexes (during and after fertile-age). Finally, female hormonal receptor status was evaluated with

immunohistochemistry on TGCT-specimens from eight women (18-50 years).

Results

Forty percent (8/20) of women with diffuse-TGCT of lower extremity reported an increase in

TGCT-related symptoms during pregnancy, predominantly an increase in swelling (62%). Mean

VAS-score on symptoms increased between 5.9 (SD 2.1) before pregnancy to 6.6 (SD 1.7) during

pregnancy. Similar results were reported in the patient-support group.

No differences were found in recurrence free survival rates, between both sexes, (localized-

(p=0.206 ≤50 years, p=0.935 >50 years); diffuse-type (p=0.664 ≤50 years, p=0.140 >50 years)),

neither in pre- versus post-menopausal women (localized- (p=0.106); diffuse-type(p=0.666)). In

all examined localized- and diffuse-TGCT tissue-samples, oestrogen or progesterone hormone-

receptor staining was negative.

Conclusion

An increase in TGCT-related symptoms during pregnancy was reported. This could not directly be

linked to female sex hormones as hormone receptors were missing histopathologically. Recurrence

free survival rates were comparable, making a relation with female sex hormones improbable.

100

Chapter five

Background

Tenosynovial Giant Cell Tumour (TGCT), previously known as Pigmented Villonodular Synovitis

(PVNS), is a rare, benign neoplasm arising from synovial joints, tendon sheaths and bursae. It

affects a relatively young population aged 30-50 years and has a slight female predominance

(male:female 1:1.5)1-3. Two subtypes are distinguished. The localized-type is defined as a single

nodule, affecting only a distinct area of the synovium with an incidence rate of 10.2 per million

person-years (excluding digits). The diffuse-type is known to be more aggressive and involves a

larger part or the entire synovial lining. It has an incidence rate of 4.1 per million person-years4, 5.

TGCT is a mono-articular disease predominantly affecting weight-bearing joints; knee (46% and

64%), hip (1% and 9%), and ankle (5% and 10%) for localized- and diffuse-type, respectively3, 4.

Pain, swelling, limited range of motion and stiffness of the affected joint are the most common

symptoms6-9. Rapid diagnosis is difficult due to these unspecific symptoms and since most

physicians are unfamiliar with the disease5, 10-12. Arthroscopic or open synovectomy is the standard

of care1, 2, 5, 8. After surgical treatment, localized-type in the knee generally follows a favourable

course with an average recurrence rate of 4 to 6% after resection (with variable follow-up). In

contrast, diffuse-type in the knee presents with multiple recurrences, on average 14% to 40% after

surgical treatment5.

In TGCT, answers on everyday questions are lacking: e.g. do hormone-based anticonceptiva

influence my disease? Does pregnancy influence the clinical behaviour of TGCT? In the outpatient

clinic and on online TGCT patient fora, an increase in TGCT-related symptoms during pregnancy

is observed. In healthy pregnant women, joint pain in the knee and hip are frequently reported13,

14. This pain is not only attributed to the additional weight. Elevated female sex hormones

(oestrogen, progesterone and the oestrogen-dependent relaxin) are known to weaken soft

tissue structures, resulting in increased joint laxity during pregnancy, joint instability and lower

extremity dysfunction13, 15, 16. To our knowledge, only two case-reports of two pregnant women

with both localized-TGCT exist (supplementary material). The first case report described a patient

diagnosed with TGCT six months after pregnancy completion, as the patient was misdiagnosed

with chondromalacia patellae17. The second patient presented with an acute onset of knee pain

during first semester of pregnancy. It was hypothesized that pregnancy-related changes triggered

torsion or bleeding of the tumour, leading to this acute presentation18. Elevated levels of oestrogen


101

5

and progesterone receptors have been identified in giant cell tumour of bone, dermatofibroma

protuberans and malignancies of breast, endometrium, ovary, prostate, colon. Hormone receptor

positive tumours show a better prognosis19-24. The presence of female sex hormone receptors in

TGCT is unknown.

This study aims to evaluate patient reported TGCT-related symptoms before and during pregnancy

in two different patient populations. Influences of sex specific hormones and female fertile life

phase specific hormones are determined by comparing recurrence free survival rates between

the sexes and pre- versus post-menopausal women. Finally, presence of female sex hormonal

receptor-status in available tumour tissue is assessed.

methods

Questionnaires in two sarcoma centres and a patient-support group

Patients with diffuse-TGCT were included, since diffuse-TGCT is a more widespread and extensive

disease, including more clinical complaints and higher recurrence rates, compared with localized-TGCT.

Two sarcoma centres

One-hundred sixty-two female patients with histopathologically proven diffuse-TGCT were

extracted from the combined Dutch TGCT-database (Leiden University Medical Centre (LUMC)

N=92 and Radboud University Medical Centre (RUMC) N=70) (figure 1)25. Excluded were seventy-

four patients <18 years or >50 years, non-weight bearing upper-extremity TGCT (elbow, wrist) or

temporomandibular localization. The remaining 88 patients were invited to complete the TGCT-

questionnaire. Incomplete questionnaires were unsuitable for analysis (N=26). Finally, sixty-two

questionnaires of patients with diffuse-TGCT of lower extremities were included.

The comprehensive TGCT-hormone questionnaire contained questions on patient- and tumour-

characteristics, initial TGCT-symptoms (prior to primary treatment), current TGCT-symptoms

(symptoms at time of questionnaire completion) and TGCT-symptoms before and during

pregnancy. To quantify TGCT-related symptoms, Visual Analogue Scale (VAS) questions were

included, ranging from 0 (no symptoms) to 10 (worst symptoms) (supplementary material). The

pregnancy questions were completed for the first pregnancy (>6 months) after TGCT-diagnosis

102

Chapter five

and questions were answered regarding the TGCT affected joint.

Patient-support group

Previously, an international crowdsourcing study was conducted in 337 patients to evaluate

impact of TGCT on daily living26. An e-survey was distributed in the largest, online support group

for TGCT-patients: the closed Facebook group ‘PVNS is pants!!’. This study contained 129 women

with diffuse-TGCT of lower extremity, aged between 18 and 50 years (figure 2). Besides patient-

and tumour characteristics, the e-survey contained validated questionnaires on physical function

and quality of life. Furthermore, questions on TGCT-related symptoms and intensity of symptoms,

pregnant at time of TGCTN=20

not pregnant at time of TGCT

N=42

RUMCN=70

Excluded (N=74)• <18 or >50 years, N=70• upper-extremity, N=3• Temporomandibular, N=1

LUMCN=92

diffuse-TGCTN=162

eligible for questionnaireN=88

Excluded (N=26)• incomplete questionnaire

or duplicate entries, N=26completed questionnaires

N=62

Figure 1 Inclusion flowchart of diffuse-TGCT women, treated in one of two sarcoma centres.

RUMC, Radboud University Medical Centre; LUMC, Leiden University Medical Centre.


103

5

before and during pregnancy were included for women only. These questions were not previously

published (supplementary material). In more than one pregnancy, questions were answered for the

pregnancy that most affected the TGCT-related symptoms.

NetQuestionnair (NetQ), an online, professional survey software supported by the LUMC, was

used to distribute and complete the questionnaires for the two sarcoma centers (eight months

available) and the patient-support support group (six months available). Both questionnaires were

approved by the institutional review board from the LUMC (comprehensive TGCT-questionnaire

study registration number P13.029 and patient support group e-survey study P16.232). NetQ

Figure 2 Inclusion flowchart of the patient-support group.

completed questionnairesN=337

diffuse-type TGCTN=237

localized-type TGCTN=72

unknown-type TGCTN=28

femalesN=186

malesN=51

Excluded (N=57)• <18 or >50 years, N=52• upper-extremity, N=5

diffuse-TGCT femalesN=129



104

Chapter five

automatically captured questionnaire-answers into an SPSS 23 file (Statistical Package for Social

Sciences statistics (SPSS®) Version 23 (Chicago, IL, USA)), only accessible to TGCT researchers.

Unique site visitors were determined by IP addresses. When duplicate entries were detected,

the most recent one was included. Statistical analyses were mainly descriptive. To verify that

diffuse-type women with increased TGCT-symptoms during pregnancy were comparable with

diffuse-type women not pregnant during TGCT in the patient support group, chi-square tests

were used for TGCT localization (knee versus hip, ankle and foot), initial surgery (arthroscopy

versus open synovectomy), recurrence (yes versus no) and total number of surgeries (1 surgery

versus ≥2 surgeries). Independent t-tests were used to compare continuous scores of validated

questionnaires on physical function and quality of life.

Comparison of recurrence free survival rates

Recurrence was defined as new disease presence after synovectomy or growing residual disease

(diagnosed on follow-up MR scan). To determine influences of sex specific hormones and female

fertile life phase specific hormones, recurrence free survival rates between the sexes and pre-

versus post-menopausal in women were assessed as a proxy. The combined database of two

sarcoma centres (LUMC and RUMC) in The Netherlands (N=455, 262 diffuse-TGCT) was used25.

This dataset contained all consecutive patients surgically treated for histopathologically proven

TGCT between 1990 to 2017. Fertile life phase was defined between 16 and ≤50 years at primary

diagnosis, since median age at natural menopause ranges between 49 and 52 years27.

Using SPSS®, recurrence free survival rate after index operation was calculated through Kaplan-

Meier survival method and log rank test in male and female patients ≤50 years and >50 years for

localized- and diffuse-type separately. Similarly, recurrence free survival rates in pre- versus post-

menopausal women were compared.

Female hormone-receptors in TGCT

Immunohistochemistry was performed on paraffin-embedded pathological specimens of

histopathologically proven TGCT tissue, obtained from eight randomly selected women between

18 and 50 years to determine female hormone receptor status. All samples were of primary

resected localized- (N=4) or diffuse-TGCT (N=4), located in the lower extremity (hip, knee, ankle).

Monoclonal Rabbit Anti-Human Oestrogen receptor α and monoclonal mouse anti-human


105

5

progesterone receptor were used (supplementary material). Hormone receptor status was assessed

in the LUMC by a dedicated pathologist, specialized in bone and soft tissue tumours. Slides were

verified with positive controls of women with oestrogen or progesterone receptor positive breast

cancer.

results

Questionnaires in two sarcoma centres and a patient-support group

Two sarcoma centres

Sixty-two women with diffuse-TGCT of the lower extremities ((knee 50 (81%), hip 6 (9%) and ankle/

foot 6 (9%)) with a median age at diagnosis of 30 (IQR 25-38) years completed the comprehensive

Dutch questionnaire (Table 1). Twenty (32%) patients were pregnant after being diagnosed with

TGCT. Eight (40%) of these patients self-reported an increase, two (10%) a decrease of symptoms and

10 (50%) continued at the same level (Table 2). TGCT-related symptoms included pain, swelling and

limited range of motion of the affected joint, swelling was predominantly increased (62%) (Table 3). In

patients with increasing symptoms, mostly during second or third trimester (5/8 (63%)) of pregnancy,

mean VAS score increased from 5.9 (SD 2.1) before pregnancy to 6.6 (SD 1.7) during pregnancy.

Patient-support group

In 129 women, median age at time of diagnosis was 30 (IQR 24-39) years and TGCT was mostly

located in the knee (93 (72%)) (Table 1). Thirty-five (27%) women had TGCT during pregnancy.

Twenty-three (66%) pregnant women stated an increase, 3/35 (9%) a decrease and 9/35 (26%) did

not experience a difference in symptoms during pregnancy. Of all reported symptoms, swelling

(57%) of the associated joint increased the most. Additional symptoms included pain, limited

range of motion and stiffness (Table 3). Self-reported intensity of TGCT-related symptoms after

pregnancy was compared with reported intensity of symptoms before pregnancy; in 10/26 (38%)

intensity increased, 6/26 (23%) intensity decreased and in 10/26 (38%) intensity continued at a

comparable level. No differences were detected in patient- and tumour-characteristics in women

with increased TGCT-symptoms during pregnancy compared with women not pregnant during

TGCT (Supplementary material; Table 1).

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Chapter five

Table 1 Tumour- and patient-characteristics of female diffuse-TGCT patients, from two sarcoma

centres* and a patient-support group**.

Sarcoma centresn (%)

Support groupn (%)

Total number of women

TGCT-localizationKneeHipAnkle/Foot

Initial symptoms PainSwellingLimited range of motionStiffness

Current symptoms PainSwellingLimited range of motionStiffness

Pregnant >6 months TotalIncreased symptomsDecreased symptoms

62 (100)

50 (81)6 (9)6 (9)

38 (61)50 (81) 32 (52)22 (36)

36 (58)23 (37)31 (50)22 (36)

20 (32)8/20 (40)2/20 (10)

129 (100)

93 (72)18 (14)18 (14)

109 (85)103 (80)83 (64)74 (57)

98 (76)76 (59)88 (68)84 (65)

35 (27)23/35 (66)

3/35 (9)

Median (IQR) Median (IQR)

Age at time of diagnosis (years)Age at time of questionnaire (years)

30 (25-38)38 (32-43)

30 (24-39)38 (30-45)

Initial symptoms, symptoms of the affected joint prior to primary treatment; Current symptoms, symptoms at time of questionnaire completion. *Leiden University Medical Centre (LUMC) and Radboud University Medical Centre (RUMC). **Largest, online patient support group for TGCT-patients: the closed Facebook group ‘PVNS is pants!!’


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5

Table 2 Patient- and tumour characteristics of eight women with increased diffuse-TGCT related

symptoms during pregnancy.

Patient Joint

Age at pregnancy

(years)

Time of TGCT

diagnosis before

pregnancy$ (months)

TGCT treatments

prior pregnancy

Most prominent increasing symptom

during pregnancy

TGCT treatments

after pregnancy

Last follow-up

status++

1 Hip 23 84+

OS + 90Yttrium,

OS + cryosurgery

Limited ROM Residual disease

2 Knee 29 36

2x OS two-staged, OS one-staged + nilotinib +

RT 56 Gy

Swelling EPR NED

3 Knee 30 24$$ AS Swelling AS NED

4 Knee 31 96 Limited ROM AS, OS*NED,

osteo-arthritis

5 Knee 34 12$$$ AS Swelling PLX, OS two-staged

Too shortly

after OS

6 Knee 34 84 AS Swelling 2012 OS Residual disease

7 Ankle 37 2 Pain OS during pregnancy

Residual disease

8 Knee 38 6 Swelling OS NED

TGCT, tenosynovial giant cell tumour; AS, arthroscopic synovectomy; OS, open synovectomy; PLX, PLX3397/pexidartinib; EPR, endoprosthetic reconstruction; Limited ROM, limited range of motion; NED, no evidence of disease. $Pregnancies were uncomplicated, unless otherwise specified. +Pregnancy was prematurely terminated because of major pain complaints of hip. ++Last follow-up >2 years since last treatment, unless otherwise specified. $$B12 deficiency, right after pregnancy locking of affected knee. $$$Had to stop TNF-α-inhibitor (indicated for oligoarthritis and Crohn’s disease). *Complication: abscess and sepsis.

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Chapter five

Table 3 Most prominent increased TGCT-related symptoms during pregnancy.

Sarcoma centresn (%)

Support groupn (%)

Pain 1 (13) 5 (22)

Swelling 5 (62) 13 (57)

Limited range of motion 2 (25) 3 (13)

Stiffness 0 2 (8)

Total increased symptoms 8 (100) 23 (100)

All patients were requested to indicate which TGCT-symptom increased most during pregnancy. This table presents self-reported increased symptoms in 8/20 (40%) and 23/35 (66%) women with diffuse-TGCT from two Dutch sarcoma centres and the patient-support group, respectively. In both populations swelling was the most prominent symptom.

Figure 3 Recurrence free survival curve in 155 diffuse-TGCT patients ≤50 years* (p=0.664).

*Age at primary diagnosis


male 71 49 32 20 12 8 6

female 84 51 34 25 18 11 9

numbers at risk

Recu

rren

ce fr

ee s

urvi

val

male

female


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5

Figure 3 (continued) Recurrence free survival curve in 107 diffuse-TGCT patients >50 years* (p=0.140).

*Age at primary diagnosis


male 42 30 17 13 10 10 9

female 65 47 37 28 21 13 11

numbers at risk

Recu

rren

ce fr

ee s

urvi

val

male

female

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Chapter five

Comparison of recurrence free survival rates

Female recurrence free survival rates were comparable to male rates for localized-type (log rank

p=0.206 ≤50 years, p=0.935 >50 years) and diffuse-type (log rank p=0.664 ≤50 years, p=0.140 >50

years) (figure 3). Similarly, in women during and after fertile age, recurrence free survival rates were

comparable for localized-type (log rank p=0.106) and diffuse-type (log rank p=0.666).

Female hormone-receptors in TGCT

All eight localized- and diffuse-TGCT tissue samples were oestrogen or progesterone hormone

receptor negative. Further evaluation of additional patient samples was therefore deemed

unnecessary.

discussion

This is the first study to evaluate hormonal influences on the clinical presentation of Tenosynovial

Giant Cell Tumour (TGCT). An increase in TGCT-related symptoms during pregnancy was reported,

in particular swelling of the affected joint. Recurrence free survival rates were comparable for both

sexes as well as for pre- versus postmenopausal women. Oestrogen and progesterone-receptors

were not present with immunohistochemistry in TGCT tissue.

In the current study, 56% (31/55) of pregnant patients reported an increase in TGCT-related

symptoms and a minority reported a decrease in these symptoms (9%; 5/55). Swelling of the

affected joint was self-reported as the most prominent symptom during pregnancy. Since TGCT

is a mono-articular disease, this swelling is not comparable with the clinical (bilateral) oedema

accompanying a majority of (healthy) pregnancies14. The increase in symptoms was mainly present

during second and third trimester of pregnancy. Similar, healthy pregnancy is associated with an

increase in lower extremity symptoms during these trimesters14. A valid question would be why

an increase in mono-articular TGCT swelling during pregnancy would present in these later stages

of pregnancy. Since growth hormone is already present five weeks after conception, the question

is whether growth hormone influences TGCT-related joint swelling. The experienced increase in

disease burden might be caused by progressive disease, but is more likely based on increased

effusion. Although pregnancy seems to provoke an increase in TGCT-related symptoms, this might

be coincidental according to subjective complaints, recall bias and focus on the affected joint.


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5

In general, a multifactorial aetiology is responsible for lower-extremity symptoms during healthy

pregnancy28. First; biomechanical changes, including the anterior shift of the center of gravity13,

the extra bodyweight29 and a different gait-pattern due to an increased pressure on the lateral

side of the foot30, are responsible for lower limb and functional knee pain in pregnant women. As

a consequence, a decrease in physical functioning is reported during progression of pregnancy,

also in healthy women15. Second; relaxation of joints is a physiologic process associated with

pregnancy. This increased joint-laxity and weakened soft tissue structures is mainly based on the

pregnancy initiated elevated levels of the hormone relaxin31. Third; discontinuation of medication

considered unsafe for the unborn child, for instance non-steroidal anti-inflammatory drugs

(NSAID’s) or tumour necrosis factor-blockers (TNF-α-inhibitors), might affect the experience of

TGCT-symptoms. Additional factors of possible influence on TGCT-related symptoms are nausea/

fatigue, stress, emotional/personal problems and anxiousness for additional tasks after pregnancy.

The increased TGCT-related symptoms during pregnancy might also be attributed to this

multifactorial aetiology for lower extremity symptoms during healthy pregnancy. One (1/8(13%))

patient with increased symptoms interrupted her TNF-α-inhibitor (indicated for oligoarthritis and

Crohn’s disease) (Table 2; patient 5).

To test the hypothesis that female sex hormones influence TGCT, we compared recurrence rates

for both sexes. Since oestrogen and progesterone in women decline after fertile age, recurrence

free survival rate analyses were performed for both sexes ≤50 and >50 years, without revealing

a difference. In accordance with literature no differences in recurrence rates between male and

female TGCT-patients were found32. To our knowledge, pre- versus post-menopausal analyses had

not been performed before and yielded also no difference.

In all eight primary resected TGCT-tissues, oestrogen or progesterone receptors were completely

absent. This is a small sample size, although it is unlikely that positive female sex hormone status

will be detected by evaluating additional specimens. Hormone-based anticonceptica or female

hormone based treatments do not seem to influence the clinical behaviour of TGCT. Future

research is recommended to find the cause of increased symptoms in TGCT during pregnancy

and to contribute to possible new treatment modalities, e.g. growth-factor, ED-A fibronectin

(expressed during embryogenesis) or changes in the auto-immune system.

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Chapter five

Evaluation of hormonal influences in TGCT is challenging because of the rarity of the tumour

and the heterogeneous patient population. Main limitation in our two questionnaire studies

was participant recall bias. Information provided on a recall basis diminishes the accuracy of

results. Preferably, an observational study would be performed, including a control group and

radiographic evaluation of tumour severity before and after pregnancy. Furthermore, answers from

the e-survey in the patient support group could be influenced by multicultural differences. Finally,

while previous surgeries provoke deteriorated clinical outcome, treatments before pregnancy and

treatment phase during pregnancy were not taken into consideration.

conclusion

In conclusion, an increase in TGCT-related symptoms during pregnancy was reported in two

different patient cohorts. This could not directly be linked to female sex hormones as hormone

receptors were missing histopathologically. Recurrence free survival rates between both sexes and

between pre- versus post-menopausal women were also comparable, making a causal relation

with female sex hormones even more unlikely.


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joint preserving therapy. Arch Orthop Trauma Surg. 2017.

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synovitis of the hip. J Bone Joint Surg Am. 2005;87(5):1019-24.

12. Gonzalez Della Valle A, Piccaluga F, Potter HG, Salvati EA, Pusso R. Pigmented villonodular synovitis of the hip: 2- to 23-

year followup study. Clin Orthop Relat Res. 2001(388):187-99.

13. Marnach ML, Ramin KD, Ramsey PS, Song SW, Stensland JJ, An KN. Characterization of the relationship between joint

laxity and maternal hormones in pregnancy. Obstet Gynecol. 2003;101(2):331-5.

14. Vullo VJ, Richardson JK, Hurvitz EA. Hip, knee, and foot pain during pregnancy and the postpartum period. J Fam Pract.

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15. Ostensen M, Fuhrer L, Mathieu R, Seitz M, Villiger PM. A prospective study of pregnant patients with rheumatoid arthritis

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16. Bridges AJ, Smith E, Reid J. Joint hypermobility in adults referred to rheumatology clinics. Ann Rheum Dis. 1992;51(6):793-

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synovitis-a case report. Knee. 2004;11(4):327-9.

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estrogen receptor, progesterone receptor, and 1,25-dihydroxyvitamin D3 receptor in breast cancer and relationship to

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21. Ciocca DR, Puy LA, Fasoli LC. Study of estrogen receptor, progesterone receptor, and the estrogen-regulated Mr 24,000

protein in patients with carcinomas of the endometrium and cervix. Cancer research. 1989;49(15):4298-304.

22. Demertzis N, Kotsiandri F, Giotis I, Apostolikas N. Giant-cell tumors of bone and progesterone receptors. Orthopedics.

2003;26(12):1209-12.

23. Kieback DG, Press MF, Atkinson EN, Edwards GL, Mobus VJ, Runnebaum IB, et al. Prognostic significance of estrogen

receptor expression in ovarian cancer. Immunoreactive Score (IRS) vs. Composition Adjusted Receptor Level (CARL).

Anticancer research. 1993;13(6b):2489-96.

24. Parlette LE, Smith CK, Germain LM, Rolfe CA, Skelton H. Accelerated growth of dermatofibrosarcoma protuberans during

pregnancy. Journal of the American Academy of Dermatology. 1999;41(5 Pt 1):778-83.

25. Mastboom MJL, Verspoor FGM, Uittenbogaard D, Schaap GR, Jutte PCH, Schreuder HWB, et al. Tenosynovial Giant Cell

Tumors in Children: A Similar Entity Compared With Adults. Clinical Orthopaedics and Related Research. 2018.

26. Mastboom MJL, Planje R, van de Sande MAJ. The patient perspective on the impact of Tenosynovial Giant Cell Tumors on

daily living. Crowdsourcing study on physical function and quality of life in 337 patients from 30 countries. Interactive

Journal of Medical Research. 2018.

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Organization Collaborative Study of Neoplasia and Steroid Contraceptives. Am J Epidemiol. 1998;148(12):1195-205.

28. Ponnapula P, Boberg JS. Lower extremity changes experienced during pregnancy. J Foot Ankle Surg. 2010;49(5):452-8.

29. Spahn G, Lesser A, Hofmann GO, Schiele R. [Knee-related Pain Problems during Pregnancy Correlate with an Increase in

Body Weight. Results of a Prospective Study]. Z Geburtshilfe Neonatol. 2015;219(5):213-9.

30. Nyska M, Sofer D, Porat A, Howard CB, Levi A, Meizner I. Planter foot pressures in pregnant women. Isr J Med Sci.

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cH

ild

ren

tenosynovial giant cell tumours

in children

chap

ter

six

a similar entity compared with adults

M.J.L. Mastboom1, F.G.M. Verspoor2, D. Uittenbogaard1, G.R. Schaap3, P.C. Jutte4, H.W.B. Schreuder2, M.A.J. van de Sande1



2 Orthopaedic Surgery, Radboud University Medical Centre, Radboud, the Netherlands

3 Orthopaedic Surgery, Academic Medical Centre Amsterdam, Amsterdam, the Netherlands

4 Orthopaedics Surgery, University Medical Centre, Groningen, Groningen, the Netherlands

Tenosynovial giant cell tumours in children

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abstract

Background

Tenosynovial Giant Cell Tumour (TGCT) is a rare, benign, monoarticular entity. Many case-series

in adults are described, whereas TGCT is only incidentally reported in children. Therefore, its

incidence rate and natural history in children are unknown.

Questions/purposes

(1) How many cases have been reported of this condition, and what were their characteristics?

(2) What is the standardized paediatric incidence rate for TGCT?

(3) Is there a clinical difference in TGCT between children and adults?

(4) What is the risk of recurrence after open resection in children compared with adults?

Methods

Data were derived from three sources: (1) a systematic review on TGCT in children, seeking

sources published between 1990 and 2016, included 17 heterogeneous, small case-series; (2) the

nationwide TGCT incidence study: the Dutch paediatric incidence rate was extracted from this

nationwide study by including patients younger than 18 years of age. This registry-based study,

in which eligible patients with TGCT were clinically verified, calculated Dutch incidence rates for

localized and diffuse-type TGCT in a 5-year timeframe. Standardized paediatric incidence rates

were obtained by using the direct method; (3) from our nationwide bone and soft tissue tumour

data registry, a clinical data set was derived. Fifty-seven children with histologically proven TGCT of

large joints, diagnosed and treated between 1995 and 2015, in all four tertiary sarcoma centres in

The Netherlands, were included. These clinically collected data were compared with a retrospective

database of 423 adults with TGCT. Chi square test and independent t-test were used to compare

children and adults for TGCT type, sex, localization, symptoms before diagnosis, first treatment,

recurrent disease, followup status, duration of symptoms, and time to followup. The Kaplan-Meier

method was used to evaluate recurrence-free survival at 2.5 years.

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Chapter six

Results

TGCT is seldom reported because only 76 paediatric patients (39 female), 29 localized, 38 diffuse,

and nine unknown type, were identified from our systematic review. The standardized paediatric

TGCT incidence rate of large joints was 2.42 and 1.09 per million person-years in localized and

diffuse types, respectively. From our clinical data set, symptoms both in children and adults were

swelling, pain, and limited ROM with a median time before diagnosis of 12 months (range, 1-72

months). With the numbers available, we did not observe differences in presentation between

children and adults in terms of sex, symptoms before diagnosis, first treatment, recurrent disease,

followup status, or median time to followup. The 2.5-year recurrence-free TGCT survival rate after

open resection was not different with the numbers available between children and adults: 85%

(95% confidence interval [CI], 67%-100%) versus 89% (95% CI, 83%-96%) in localized, respectively

(p = 0.527) and 53% (95% CI, 35%-79%) versus 56% (95% CI, 49%-64%) in diffuse type, respectively

(p = 0.691).

Conclusions

Although the incidence of paediatric TGCT is low, it should be considered in the differential

diagnosis in children with chronic monoarticular joint effusions. Recurrent disease after surgical

treatment of this orphan disease seems comparable between children and adults. With targeted

therapies being developed, future research should define the most effective treatment strategies

for this heterogeneous disease.


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introduction

Tenosynovial Giant Cell Tumour (TGCT) is a benign, monoarticular entity. Two histologically

identical but clinically different types are distinguished: localized and diffuse lesions1. This

distinction can be made either on MRI or at the time of surgery. The localized type is defined by

the World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone of 20132 as

a well-circumscribed benign small lesion (figure 1). By contrast, the diffuse type, previously named

pigmented villonodular synovitis (PVNS), shows unclear boundaries with extensive involvement of

the entire synovial membrane and infiltrative growth through adjacent structures1 (figure 2). The

knee is the most common large joint affected by TGCT with 46% of localized and 64% of diffuse-

type TGCTs affecting that joint; the hand and wrist are the next most common joints affected by

the localized form, and the ankle and hip are the next most common joints affected by diffuse

TGCT3. Delayed diagnosis is not uncommon as a result of different nonspecific clinical signs and

symptoms4, 5, and the definitive diagnosis must be made histologically. The standard treatment

remains surgical resection, but recurrence occurs in 4% to 6% patients with localized and 14% to

40% of diffuse TGCT affecting the knee5. Histologic or radiologic risk factors for recurrent disease

are unknown.

All described case-series on TGCT concern adults, whereas TGCT is only incidentally reported

in children. Owing to the rarity of the disease, the available evidence base on TGCT contains

predominantly retrospective, relatively small cohort studies, including heterogeneous data6.

Sufficient data on paediatric patients with TGCT are lacking.

We therefore combined a systematic review with analysis from a nationwide paediatric TGCT

incidence study in The Netherlands3 and clinical data on TGCT in children and adults from four

tertiary sarcoma centres in The Netherlands to answer the following questions: (1) How many

cases have been reported of this condition, and what were their characteristics? (2) What is the

standardized paediatric incidence rate for TGCT? (3) Is there a clinical difference in TGCT between

children and adults? (4) What is the risk of recurrence after open resection in children compared

with adults?

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Chapter six

Patients and methods

Children were defined as patients younger than 18 years at presentation. Large joints were defined

as all joints proximal to the metatarsophalangeal and metacarpophalangeal joints. Data were

derived from three sources: a systematic review, the nationwide TGCT incidence study, and from

our bone and soft tissue tumour data registry.

A systematic review on TGCT in children was performed, seeking sources published between

1990 and 2016. Search terms and MeSh headings were “tenosynovial giant cell”, “diffuse type

giant cell”, “giant cell tumors”, “PVNS”, “pigmented villonodular synovitis”, and “synovitis, pigmented

villonodular” combined with “infant”, “child”, “neonat”, “pediatric”, “paediatric”, “toddler”, “teen”,

“teenager”, “juvenile”, “adolescent”, “girl”, and “boy”. A total of 619 articles were identified in PubMed,

Figure 1 Localized type TGCT: MRI of a 6-year-old boy with TGCT in his left knee. a. Sagittal T1-weighted

image showing a well-circumscribed nodular lesion at the synovial lining of the anterior knee compartment.

b. Sagittal T1-weighted spectral presaturation with inversion recovery (SPIR) image after IV gadolinium

administration shows heterogeneous enhancement.

a b


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Figure 2 Diffuse type TGCT: MRI of a 16-year-old boy with TGCT in his left knee. a. Sagittal T1-weighted turbo

spin echo (TSE) image shows extensive intra- and extra-articular villous proliferation of synovium. Posterior is a

large Baker’s cyst. b. Transversal T2-weighted TSE image with heterogeneous low to intermediate signal of the

TGCT anterior and posterior (white arrows). Baker’s cyst is shown posteriorly (bigger grey arrow).

a b

EMBASE, and Cochrane library. All titles and abstracts were screened by two independent reviewers

(MJLM, DU) including case-series with at least two TGCT paediatric patients and published in

English. Case-series without detailed data on children were excluded, resulting in a data set of 17

heterogeneous, mostly small case-series of two to six patients (Table 1). The largest study included

11 patients with localized TGCT of large joints7.

The Dutch paediatric incidence rate was extracted from the nationwide TGCT incidence study

by including patients < 18 years of age3. Standardized incidence rates were obtained by using

the direct method, applying age-specific incidence rates in each 1-year age group to the WHO

standard population (http://seer.cancer.gov). This study by Mastboom et al.3 was a registry-based

study and eligible patients with TGCT were clinically verified. Patients without histologically

proven TGCT were not included.

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Chapter six

From our national bone and soft tissue tumour data registry (PALGA), a clinical data set was derived,

including 57 patients < 18 years with (histologically proven) TGCT in large joints, treated between

1995 and 2015, in one of the four tertiary sarcoma centres in The Netherlands. Clinical, biologic,

and imaging data on TGCT type, sex, localization, age at diagnosis, symptoms before diagnosis,

treatment(s), recurrence(s), and followup were collected.

A combined retrospective database of two tertiary oncology centres (Leiden University Medical

Centre and Radboud University Medical Centre) in The Netherlands has recorded all patients with

TGCT since 1990 (455 patients). TGCT data on children were compared with TGCT data on 423

adults (32 children within this database were excluded from the adult group).

Statistical analyses, for our clinical data set, were predominantly descriptive. Chi square test was

used to compare children and adults on TGCT type, sex (male versus female), localization (knee

versus other large joints), symptoms before diagnosis (pain, swelling, and loss of function: yes

versus no), first treatment (arthroscopic resection versus open resection), recurrent disease (no

recurrence versus recurrence), and followup status. Independent t-test was used to compare

median duration of symptoms and median time to followup. All reported p values were two-

tailed. Statistical significance level was defined at p < 0.05. The recurrence-free survival curve was

assessed with Kaplan-Meier methods.

This study was approved by the institutional review board from the Leiden University Medical

Centre (medical ethical approved protocol P13.029). Data capturing and analyses were performed

at Leiden University Medical Centre. SPSS Version 23 (Chicago, IL, USA) was used for analyses.

results

Our systematic review identified 17 case-series involving 76 children (39 female) with TGCT, 29

localized, 38 diffuse, and nine unknown type (Table 1). The paediatric group ranged from 3 to 18

years of age. The knee was most frequently affected (44 [58%]). Swelling, pain, and limited ROM were

described symptoms before diagnosis (mean duration, 15 months). The majority of patients were

primarily treated with synovectomy, either arthroscopic or open. Recurrent disease was described

in 10 patients (13%). Only five paediatric studies described function or quality of life after treatment.

Patients with (multiple) recurrences experienced impaired function and quality of life, according to

van der Heijden et al.22. Five children with diffuse TGCT, described by de Visser et al.13, had fair to


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excellent results on the Musculoskeletal Tumour Society (MSTS) score after surgical treatment (MSTS

by Enneking). Gholve et al.7 described 11 children with surgically treated localized TGCT without

disabling joint function according to a telephone questionnaire survey. Seven surgically treated

children, described by Baroni et al.4, recovered full ROM and two patients showed impaired joint

movement with occasional mild to moderate pain in four children with localized and five children

with diffuse type. Nakahara et al.21 showed three children with diffuse disease of the knee with almost

maximum Knee Society Scores and improved postoperative ROM of at least 0° to 145°.

The standardized paediatric TGCT incidence rate of large joints was 2.42 and 1.09 per million person-

years in localized and diffuse types, respectively3. Between 2009 and 2013, 53 children with localized

TGCT (excluding digits) and 24 children with diffuse TGCT were diagnosed in The Netherlands. This

resulted in a Dutch incidence rate of 2.86 per million person-years for localized TGCT (excluding digits)

and 1.30 per million person-years for diffuse TGCT; this was converted to standardized incidence

rates (Supplemental Table 1 [Supplemental materials are available with the online version of CORR®.]). In

both localized and diffuse types, the knee was most commonly affected (Figure 3).

Clinical data of TGCT in children from the four Dutch tertiary sarcoma centres seemed similar to those

observed in the combined two Dutch retrospective adult databases (Table 2). Fifty-seven children

(median age at diagnosis, 16 years; range, 4-18 years) with TGCT of large joints were identified (Table

2). Symptoms before diagnosis were swelling, pain, and limited ROM with a median duration of 12

months (range, 1-72 months). These symptoms and the diagnostic delay seemed similar to those

observed in adults (Table 2). Children showed a localized diffuse ratio of one to one; the knee was

predominantly affected (13 of 28 [46%] localized, 19 of 29 [66%] diffuse) and there was a predilection

for females (15 of 28 [54%] localized, 18 of 29 [62%] diffuse). In 423 adults, the localized:diffuse ratio

was 1:1.6; the knee was predominantly affected (121 of 172 [70%] localized, 189 of 251 [75%] diffuse)

with a predilection for females (107 of 172 [62%] localized, 142 of 251 [57%] diffuse).

Recurrence-free survival curves were not different with the numbers available between children

and adults at the four involved tumour centres (Figure 4). The 2.5-year recurrence-free survival,

after surgical treatment, in paediatric patients compared with adults was 85% (95% confidence

interval [CI], 67%-100%) versus 89% (95% CI, 83%-96%; p = 0.527) in localized and 53% (95%

126

Chapter six

Table 1 Literature overview on TGCT affecting all joints in children, including at least two

TGCT cases (1990-2016, English language)*

Study Year Number Sex Mean age (years; range)

Symptoms before

diagnosis

Mean duration of symptoms

(months; range)TGCT type Joint Primary

surgeriesRecurrent

diseaseMean followup

(months; range)

Givon8 1991 2 1 M, 1 F 7 (7-7) S, W, LROM 60 (both patients) 1 L, 1 D 2 knee 1 AS, 1 US 0 24 (12-36)

Rosenberg† 9 2001 2 2 M 12 (10-14) S NA 1 L, 1 D 2 knee 1 OS, 1 US NA NA

Neubauer|| 10 2007 5 3 M, 2 F 12 (8-15) S,P 10 (2-24) 5 unknown 4 knee, 1 ankle 5 AS 1 36 (12-84)

Gholve et al.|| 7 2007 11 6 M, 5 F 12 (7-16) S, P 10 (1-24) 11 L 2 knee, 3 ankle, 4 foot, 1 hand, 1 wrist 11 OS 0 54 (15-130)

Pannier† 11 2008 6 2 M, 4 F 12‡ NA NA 2 L, 4 D 5 knee, 1 ankle 5 US, 1 MT 2 58‡

Baroni et al. 4 2010 9 4 M, 5 F 11 (7-15)¶ S, P, LROM 18 (2-48) 4 L, 5 D 9 knee 4 AS, 5 OS 0 82 (46-143)

Current 2017 57 24 M, 33 F 14 (4-18) S, P, LROM 16 (1-72) 28 L, 29 D 32 knee, 11 ankle, 5 foot, 4 hip, 2 hand, 2 other, 1 wrist 9 AS, 47 OS, 1 WS 23 55 (0-260)

Also adult cases included

Abdul-Karim 12 1992 2 2 M 10 (10-10) S, P NA 2 D 1 foot, 1 ankle 1 US, 1 AP 0 132 (108-156)

de Visser et al. 13 1999 5 4 M, 1 F 16 (12-18) NA NA 5 D 4 knee, 1 ankle 4 US, 1 RS 5 residual disease 30 (21-75)

Perka 14 2000 2 2 F 12 (8-16) S, P, LROM 12‡ 2 L 2 knee 2 US 0 NA

Somerhausen 15 2000 4 3 M, 1 F 14 (3-18) S 7 (6-8) 4 D 1 knee, 1 foot, 1 buttock, 1 thigh 4 US 0/1 NA 44.5 (0-114)

Gibbons 16 2002 3 1 M, 2 F 11 (8-15) S 28 (6-96)§ 3 L 3 foot 3 US 0 NA

Bisbinas 17 2004 5 5 F 14 (12-15) S 2‡ 5 L 5 ankle 5 OS 0 46 (12-150)

Brien 18 2004 3 1 M, 2 F 13 (12-15) S, P 7 (1-24)§ 3 D 2 foot, 1 ankle 3 US 2 NA

Sharma 19 2006 4 2 M, 2 F 14 (8-17) S, P 2‡ 4 unknown 4 ankle 4 US 0 37.5 (19-65)

Sharma 20 2007 3 2 M, 1 F 17 (16-18) S, P 5 (2-9) 3 D 3 knee 3 OS 1 96 (54-138)

Nakahara et al. 21 2012 3 2 M, 1 F 11 (8-13) NA NA 3 D 3 knee 3 OS 0 29 (20-36)

van der Heijden 22 2014 7 2 M, 5 F 14 (6-18) NA NA 7 D 7 knee 4 AS, 3 OS 4 95 (24-212)

Total 133 57 L, 67 D, 9 unknown


127

6

Table 1 Literature overview on TGCT affecting all joints in children, including at least two

TGCT cases (1990-2016, English language)*

Study Year Number Sex Mean age (years; range)

Symptoms before

diagnosis

Mean duration of symptoms

(months; range)TGCT type Joint Primary

surgeriesRecurrent

diseaseMean followup

(months; range)

Givon8 1991 2 1 M, 1 F 7 (7-7) S, W, LROM 60 (both patients) 1 L, 1 D 2 knee 1 AS, 1 US 0 24 (12-36)

Rosenberg† 9 2001 2 2 M 12 (10-14) S NA 1 L, 1 D 2 knee 1 OS, 1 US NA NA

Neubauer|| 10 2007 5 3 M, 2 F 12 (8-15) S,P 10 (2-24) 5 unknown 4 knee, 1 ankle 5 AS 1 36 (12-84)

Gholve et al.|| 7 2007 11 6 M, 5 F 12 (7-16) S, P 10 (1-24) 11 L 2 knee, 3 ankle, 4 foot, 1 hand, 1 wrist 11 OS 0 54 (15-130)

Pannier† 11 2008 6 2 M, 4 F 12‡ NA NA 2 L, 4 D 5 knee, 1 ankle 5 US, 1 MT 2 58‡

Baroni et al. 4 2010 9 4 M, 5 F 11 (7-15)¶ S, P, LROM 18 (2-48) 4 L, 5 D 9 knee 4 AS, 5 OS 0 82 (46-143)

Current 2017 57 24 M, 33 F 14 (4-18) S, P, LROM 16 (1-72) 28 L, 29 D 32 knee, 11 ankle, 5 foot, 4 hip, 2 hand, 2 other, 1 wrist 9 AS, 47 OS, 1 WS 23 55 (0-260)

Also adult cases included

Abdul-Karim 12 1992 2 2 M 10 (10-10) S, P NA 2 D 1 foot, 1 ankle 1 US, 1 AP 0 132 (108-156)

de Visser et al. 13 1999 5 4 M, 1 F 16 (12-18) NA NA 5 D 4 knee, 1 ankle 4 US, 1 RS 5 residual disease 30 (21-75)

Perka 14 2000 2 2 F 12 (8-16) S, P, LROM 12‡ 2 L 2 knee 2 US 0 NA

Somerhausen 15 2000 4 3 M, 1 F 14 (3-18) S 7 (6-8) 4 D 1 knee, 1 foot, 1 buttock, 1 thigh 4 US 0/1 NA 44.5 (0-114)

Gibbons 16 2002 3 1 M, 2 F 11 (8-15) S 28 (6-96)§ 3 L 3 foot 3 US 0 NA

Bisbinas 17 2004 5 5 F 14 (12-15) S 2‡ 5 L 5 ankle 5 OS 0 46 (12-150)

Brien 18 2004 3 1 M, 2 F 13 (12-15) S, P 7 (1-24)§ 3 D 2 foot, 1 ankle 3 US 2 NA

Sharma 19 2006 4 2 M, 2 F 14 (8-17) S, P 2‡ 4 unknown 4 ankle 4 US 0 37.5 (19-65)

Sharma 20 2007 3 2 M, 1 F 17 (16-18) S, P 5 (2-9) 3 D 3 knee 3 OS 1 96 (54-138)

Nakahara et al. 21 2012 3 2 M, 1 F 11 (8-13) NA NA 3 D 3 knee 3 OS 0 29 (20-36)

van der Heijden 22 2014 7 2 M, 5 F 14 (6-18) NA NA 7 D 7 knee 4 AS, 3 OS 4 95 (24-212)

Total 133 57 L, 67 D, 9 unknown

*Large joints were defined as all joints proximal to and excluding metatarsophalangeal and metacarpophalangeal

joints; large case-series not describing children in detail were not included; †language of article was French; included

information is based on an English abstract; ‡range unavailable; §including adult cases; ||TGCT cases in digits were

excluded; ¶case number 6, a 2-year-old girl, was excluded according to a delayed time to diagnosis of 38 months;

TGCT = tenosynovial giant cell tumour; M = male; F = female; NA = information not available; S = swelling;

W = warmth; LROM = limited ROM; P = pain; L = localized TGCT; D = diffuse TGCT; AS = arthroscopic synovectomy;

OS = open synovectomy; US = unspecified

128

Chapter six

CI, 35%-79%) versus 56% (95% CI, 49%-64%; p = 0.691) in diffuse type, respectively. In the four

involved sarcoma centres, most children and adults alike were primarily surgically treated by open

resection: localized TGCT in 25 of 28 children (89%) were thus treated compared with 142 of 172

adults (85%; p = 0.486); for diffuse TGCT in children, the proportion was 22 of 29 (76%) compared

with 188 of 251 in adults (75%; p = 0.289). Recurrence risk in children and adults was likewise not

different with the numbers available: two of 28 (7%) compared with 22 of 172 (13%; p = 0.365)

in localized type and 11 of 29 (38%) compared with 119 of 251 (47%; p = 0.921) in diffuse type,

respectively.

Figure 3 Skeleton showing TGCT

localization in children extracted

from a Dutch incidence study,

excluding digits3. In diffuse

TGCT, one patient was classified

as “other”; he was treated for

TGCT in his vertebral column.

6%

17%

8%

47%

13%

9%

localized-TGCT diffuse-TGCT

4%

8%

4%

50%

25%

4%


129

6

Figure 4 Local recurrence-free survival curve of localized and diffuse TGCT (Kaplan-Meier), excluding

digits. Time zero is the time of the primary surgery. All patients were surgically treated; patients treated

with wait-and-see treatment are excluded. In the adult graph, two patients died and were censored at

the time of death if a recurrence had not occurred.


Loca

l rec

urre

nce

free

sur

viva

l

TGCT children compared to adults

diffuse adults

diffuse children

localized childeren

localized adults

1.0

0.8

0.6

0.4

0.2

0 2 4 6 8

0.0

130

Chapter six

Table 2 Details of patients with TGCT of large joints in children versus adults,

including sex, localization, age, symptoms, first treatment, recurrent disease, and followup†

Children Adults Children versus adults

Patient variables Localized TGCT Diffuse TGCT Localized TGCT Diffuse TGCT p value localized TGCT

p value diffuse TGCT

Total number of patients 28 29 172 251

Sex 0.285 0.434

Male:female ratio 13:15 (1:1.2) 11:18 (1:1.6) 65:107 (1:1.6) 109:142 (1:1.3)

Localization 0.019 0.207

Knee 13 (46%) 19 (66%) 121 (70%) 189 (75%)

Other joints 15 (54%) 10 (34%) 51 (30%) 62 (25%)

Age

Median age at diagnosis (years; range) 16 (4-18) 16 (11-18) 42 (19-82) 38 (19-72)

Symptoms before diagnosis

Swelling 24 (86%) 21 (72%) 106 (62%) 163 (65%) 0.010 0.510

Pain 12 (43%) 17 (59%) 103 (60%) 157 (63%) 0.129 0.558

Limited ROM 3 (11%) 4 (14%) 13 (8%) 49 (20%) 0.608 0.486

Median duration of symptoms (months; range) 9 (1-48) 18 (1-72) 12 (1-240) 24 (1-300) 0.176 0.153

First treatment 0.486+ 0.289+

Arthroscopic resection 3 (11%) 6 (21%) 7 (4%) 37 (15%)

Open resection 25 (89%) 22 (76%) 147 (85%) 188 (75%)

Wait and see 0 1 (3%) 18 (11%) 26 (10%)

Recurrent disease† N = 28 N = 28 N = 154 N = 225 0.280 0.407

No recurrence 26 (93%) 17 (61%) 132 (86%) 106 (47%)

≥ 1 recurrence 2 (7%) 11 (39%) 22 (14%) 119 (53%)

Followup status 0.840 0.768

Disease-free 19 (68%) 16 (55%) 110 (64%) 121 (48%)

Alive with disease‡ 4 (14%) 9 (31%) 19 (11%) 94 (37%)

Death of other disease 0 0 0 2 (1%)

Lost to followup‡ 5 (18%) 4 (14%) 43 (25%) 34 (14%)

Median time to followup (months; range)* 25 (7-100) 77 (7-144) 36 (6-301) 54 (6-350) 0.127 0.780


131

6

Table 2 Details of patients with TGCT of large joints in children versus adults,

including sex, localization, age, symptoms, first treatment, recurrent disease, and followup†

Children Adults Children versus adults

Patient variables Localized TGCT Diffuse TGCT Localized TGCT Diffuse TGCT p value localized TGCT

p value diffuse TGCT

Total number of patients 28 29 172 251

Sex 0.285 0.434

Male:female ratio 13:15 (1:1.2) 11:18 (1:1.6) 65:107 (1:1.6) 109:142 (1:1.3)

Localization 0.019 0.207

Knee 13 (46%) 19 (66%) 121 (70%) 189 (75%)

Other joints 15 (54%) 10 (34%) 51 (30%) 62 (25%)

Age

Median age at diagnosis (years; range) 16 (4-18) 16 (11-18) 42 (19-82) 38 (19-72)

Symptoms before diagnosis

Swelling 24 (86%) 21 (72%) 106 (62%) 163 (65%) 0.010 0.510

Pain 12 (43%) 17 (59%) 103 (60%) 157 (63%) 0.129 0.558

Limited ROM 3 (11%) 4 (14%) 13 (8%) 49 (20%) 0.608 0.486

Median duration of symptoms (months; range) 9 (1-48) 18 (1-72) 12 (1-240) 24 (1-300) 0.176 0.153

First treatment 0.486+ 0.289+

Arthroscopic resection 3 (11%) 6 (21%) 7 (4%) 37 (15%)

Open resection 25 (89%) 22 (76%) 147 (85%) 188 (75%)

Wait and see 0 1 (3%) 18 (11%) 26 (10%)

Recurrent disease† N = 28 N = 28 N = 154 N = 225 0.280 0.407

No recurrence 26 (93%) 17 (61%) 132 (86%) 106 (47%)

≥ 1 recurrence 2 (7%) 11 (39%) 22 (14%) 119 (53%)

Followup status 0.840 0.768

Disease-free 19 (68%) 16 (55%) 110 (64%) 121 (48%)

Alive with disease‡ 4 (14%) 9 (31%) 19 (11%) 94 (37%)

Death of other disease 0 0 0 2 (1%)

Lost to followup‡ 5 (18%) 4 (14%) 43 (25%) 34 (14%)

Median time to followup (months; range)* 25 (7-100) 77 (7-144) 36 (6-301) 54 (6-350) 0.127 0.780

*Patients lost to followup are excluded for median time to followup; lost to followup is defined as < 6 months

followup; †+wait and see treatment was not included in calculation of independent t-test; children were included

between 1995 and 2015 adults between 1990 and 2015; ‡patients alive with disease either have wait and see

treatment, residual or recurrent disease; TGCT = tenosynovial giant cell tumor.

132

Chapter six

discussion

TGCT is most commonly seen in adults in the third and fourth decades of life, but this study confirms

that it also affects paediatric patients. The paediatric incidence rate for both localized and diffuse

type suggests that it is rare, but we believe it is still common enough to include in the differential

diagnosis of both children and adults with nonspecific symptoms like swelling, pain, and limited

ROM. We found no differences with the numbers available between children and adults in terms

of presenting symptoms, treatments used in the few available case-series, and recurrence-free

survival rates. In the era of personalized medicine, future research should define the most effective

treatment for TGCT, with its various clinical scenarios, both in children and adults.

There are some limitations to this study. In our systematic review, many case-series included data from

children with TGCT in embedded studies that also contained adults’ data. When data on children was

not separately described, these children were not included in the overview (Table 1). The determined

incidence rate is a conservative estimate, because our search was based on the nationwide network

and registry of histo- and cytopathology in The Netherlands23. Patients with TGCT without a biopsy

or treatment were not represented in this pathology-based cohort. By standardizing incidence rates,

they could be extrapolated to other populations. However, generalizability of the standardized

incidence rate depends on the age-specific population structure of the country compared with the

WHO population. Included patients had histologically proven TGCT by a dedicated musculoskeletal

pathologist (UF, HB, AS, JB). However, patients were not centrally reviewed for this study. Neither

functional outcome nor quality of life was evaluated. For TGCT treatment, only surgical treatment

was evaluated. Future, comparative studies on treatments should determine what should be done for

patients (children and adults) with TGCT. Although surgery is the mainstay, other treatments are used,

and future research needs to define what the best approaches are for the various clinical scenarios in

which this disease presents. In our patients, children with the localized type frequently lacked longer

term followup, mainly as a result of absence of clinical symptoms (17 censored in the first 2.5 years;

Figure 4). Smaller patient numbers with the diffuse type sometimes lacked longer followup (nine

censored in the first 2.5 years).

TGCT does not seem to be an adults-only disease and should be considered in the differential

diagnosis in children with (chronic) monoarticular joint effusion. Our systematic review identified

mainly small, heterogeneous TGCT case-series in children. Future studies might consider including

children with TGCT to allow for optimalization of the treatment protocol in both children and adults.


133

6

The standardized paediatric TGCT incidence rate of large joints was 2.42 and 1.09 per million

person-years compared with an overall incidence rate of 10.2 and 4.1 per million person-years

in localized and diffuse types, respectively3. To date, the incidence rate for chronic monoarthritis

in children and adolescents is unknown. Savolainen et al. calculated an incidence rate of 64

per 100,000 for all types of arthritis in children (< 16 years) in a defined population in Finland24.

Although TGCT in children probably accounts for only a small percentage of all types of arthritis, it

should still be considered in the differential diagnosis.

Symptoms in children seemed similar to those in adults (Table 1). Nonspecific symptoms

accompanied by pain and diffuse joint swelling with thickening of the synovial capsule and/or

joint effusion resulted in limited movement in approximately half of the patients. Studies in adults

add mechanical symptoms, instability, and stiffness5, 25.

A systematic review (without age limitations) in 20135 reported average recurrence rates for

localized TGCT in the knee after open resection (4%) and after arthroscopic resection (6%) in

contrast to diffuse type after open resection (14%) and after arthroscopic resection (40%) at a

mean followup of 108 months. Patel et al.25 presented 214 patients with knee TGCT of all ages with

a recurrence rate of 9% in 100 localized patients and 48% in 114 patients with diffuse TGCT after a

mean followup of 25 months (range, 1-168 months). Palmerini et al.26 reported 294 patients with

TGCT of all ages in all joints with a local failure rate of 14% in localized and 36% in diffuse type after

a median followup of 4.4 years (range, 1-20 years). The sole primary disease or patients with a first

relapse were included. The current paediatric case-series showed comparable recurrence rates of

7% in localized and 39% in diffuse type after a mean followup of 55 months (range, 7-350 months).

TGCT is a rare condition in adults and it is even less common in children. Nonspecific symptoms

often contribute to a delay in establishing a diagnosis. TGCT should be considered in chronic

monoarthritis both in adults and in children. Recurrent disease after surgical treatment of this

orphan disease seems comparable between children and adults. With targeted therapies now

being developed27, future research should define the most effective treatment strategies for this

heterogeneous disease.

Supplementary data

Supplementary data are available in the online version of this article:

https://dx.doi.org/10.1007/s11999.0000000000000102

134

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cases with extraarticular disease. The American journal of surgical pathology. 2000;24(4):479-92.

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24. Savolainen E, Kaipiainen-Seppanen O, Kroger L, Luosujarvi R. Total incidence and distribution of inflammatory

joint diseases in a defined population: results from the Kuopio 2000 arthritis survey. The Journal of rheumatology.

2003;30(11):2460-8.







loca

lize

dsurgical treatment

of localized-type tenosynovial giant

cell tumours of large joints

chap

ter

seve

n

a multicentre-pooled database of 31 international sarcoma centres

M.J.L. Mastboom1, E.L. Staals2, F.G.M. Verspoor3, A.J. Rueten-Budde4, S. Stacchiotti5, E. Palmerini6, G.R. Schaap7, P.C. Jutte8,

W. Aston9, A. Leithner10, D. Dammerer11, A. Takeuchi12, Q. Thio13, X. Niu14, J.S. Wunder15, TGCT study-group*, M.A.J. van de Sande1

Submitted.

1 Orthopaedic Surgery, Leiden University Medical Center, Leiden, The Netherlands

2 Orthopaedic Surgery, Musculoskeletal Oncology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

3 Orthopaedic Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

4 Mathematical institute, Leiden University, Leiden, The Netherlands

5 Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

6 Medical Oncology, Musculoskeletal Oncology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

7 Orthopaedic Surgery, Academic Medical Center, Amsterdam, The Netherlands

8 Department of Orthopaedics, University Medical Center, University of Groningen, Groningen, The Netherlands

9 Orthopedic surgery, Royal National Orthopedic Hospital, London, the United Kingdom

10 Department of Orthopaedic Surgery, Medical University Graz, Graz, Austria

11 Orthopedic surgery, Medical University of Innsbruck, Innsbruck, Austria

12 Orthopaedic surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

13 Orthopedic surgery, Massachusetts General Hospital Harvard, Boston, United States of America

14 Department of Orthopedic Oncology, Beijing Jishuitan Hospital, Beijing, 100035, China

15 University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada

*TGCT study-group:

M. Fiocco, H. Gelderblom, P.D.S. Dijkstra, R.J.P. van der Wal, P.A. Daolio, P. Picci, A. Gronchi, S. Ferrari, H. Özger, R.G.

Maki, H.W.B. Schreuder, I.C.M. van der Geest, J.A.M. Bramer, M. Boffano, E. Goldenitsch, D. Campanacci, P. Cuomo,

P.C. Ferguson, A.M. Griffin, Y. Sun, T. Schubert, K. Patel, M.S.J. Aranguren, A. Blancheton, F. Gouin, H.R. Dürr, C.F.

Capellen, J. Schwab, S. Iwata, O. Vyrva, W. Weschenfelder, E.H.M. Wang, M. Wook Joo, Y.K. Kang, Y.G. Chung, W.

Ebeid, J. Bruns, T. Ueda

Localized-type tenosynovial giant cell tumours

139

7

abstract

Background

Localized-type Tenosynovial Giant Cell Tumour (TGCT) is a rare, neoplastic disease with only limited

data supporting treatment protocols. A multicentre-pooled collection of individual patient data

resulted in the largest global retrospective cohort of localized-TGCT patients to date. We describe

treatment protocols and evaluate their oncological outcome, complications and functional results.

A secondary study aim was to identify risk factors for local recurrence after surgical treatment.

Methods

Patients with histologically proven localized-TGCT of large joints were included if treated between

1990-2017 in one of 31 tertiary sarcoma centres. In 941 patients with localized-TGCT, 62% were female,

median age at initial treatment was 39 years with a median follow-up of 37 months. 67% affected the

knee and the primary treatment at a tertiary centre was one-staged open resection in 73%. Proposed

risk factors were tested in a univariate analysis and significant factors subsequently included for

multivariate analysis, with an endpoint of first local recurrence after treatment in a tertiary centre.

Results

Recurrent disease developed in 12% of all cases, with local recurrence free survival rates at 3, 5

and 10 years of 88%, 83% and 79%, respectively. The strongest risk factor for recurrent disease was

prior recurrence (p<0.001). Complications were noted in 4% after surgical treatment of localized-

TGCT. Initial symptoms of pain and swelling improved after surgical treatment(s) in 71% and

85%, respectively. For therapy naïve cases, univariate and multivariate analyses yielded positive

associations with local recurrence for tumour size ≥5 cm vs <5 cm (HR 2.50; 95%CI 1.32-4.74; p=0.005)

and initial treatment with arthroscopy vs open resection (HR 2.18; 95%CI0.98-4.84; p=0.056).

Conclusions

Risk factors for recurrent disease after resection of localized-type TGCT were larger tumour size

and initial treatment with arthroscopy. Relatively low complication rates and good functional

outcome warrant an open approach with complete resection when possible, to reduce recurrence

rates in high risk patients.

140

Chapter seven

introduction

In 2013 the WHO defined Tenosynovial Giant Cell Tumours (TGCT), after unification of Giant

Cell Tumour of the Tendon Sheath and Pigmented Villonodular Synovitis (PVNS), as a benign

mono-articular disease, arising from the synovial lining of joints, bursae or tendon sheaths in

predominantly young adults1, 2.

Clinically and radiographically, TGCT is subdivided into a lobulated often well-bordered lesion

(localized-type) that does not involve the surrounding (teno-)synovial lining and a more

aggressive lesion, involving a large part or all of the synovial lining (diffuse-type)1-3. Despite

sharing the same histopathology and genetics, the natural course of disease in localized- and

diffuse-TGCT is incomparable and necessitate a separate assessment of treatment protocol and

surgical outcome. Based on anatomical site of the localized-type tumour, differentiation is made

between disease affecting digits and disease occurring in and about larger joints4-6. The present

study focuses on localized-TGCT of large joints (figure 1), most commonly affecting the knee or

other weight bearing joints1, 2, 6, 7.

The macroscopic appearance of localized-TGCT is typically a well-circumscribed lobulated lesion,

with white to grey, yellow and brown mottled areas. According to the WHO, localized-TGCT is a

small lesion, with a size range of 0.5 to 4 cm1, 2. However, according to the authors’ experience, the

largest size can frequently exceed 4 cm, especially when compressed in relatively tight joints (e.g.

foot and ankle) or situated in the anterior or posterior aspect of the knee.

The main patients complaints related to localized-TGCT include pain, joint effusion, stiffness,

locking and limited range of motion8, 9. The predominant standard of care for localized-TGCT is

surgical resection of the tumour, in order to: (1) reduce debilitating symptoms and prevent joint

destruction caused by local compression of cartilage; (2) improve limb function; and (3) minimize

the risk of local recurrence. Clinical and oncological outcomes following surgery depend on

multiple factors including the localization and extent of disease and possibly the technical

experience of the surgeons3, 7, 10-12.

The current literature mainly consists of relatively small, or larger but heterogeneous case-series,


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7

as localized-TGCT of large joints is an orphan disease, with an incidence of 10.2 per million person-

years6. A systematic review, including predominantly small case-series up to ten patients, showed

comparable recurrence rates after arthroscopic and open resection of the knee (6% versus 4%,

respectively)13. However, studies included in this review had different follow-up times ranging

from not available to 18, up till 112 months. Complications and functional outcomes after surgical

treatment are only sparsely reported and surgical treatment by arthroscopic or open resection for

localized-TGCT at present remains a matter of debate7-9, 14-16.

Evaluation of a large number of individual patients is preferred to evaluate the best treatment

strategy and possibly identify risk-factors for recurrent disease. Individual participant data meta-

analysis offers advantages, above a meta-analyses, as missing data can be accounted for at the

individual level, subgroup analyses can be performed (e.g. per affected joint) and follow-up

information can be updated17. Therefore, we aimed to collaborate with tertiary sarcoma centres all

over the world to include individual participant data of TGCT affecting large joints.

The primary aim of this international multicentre cohort study is to provide comprehensive and

up to date insights on TGCT surgical treatment as well as oncologic and functional outcomes

and complications in this largest global retrospective cohort of patients with localized-TGCT.

Secondarily, risk factors for local recurrence after surgical treatment are identified.

methods

Recruitment and inclusion criteria

Patients with histologically proven TGCT of large joints were included if treated between 1990 and

2017 in one of 31 sarcoma centres globally (supplementary material). Large joints were defined as

all joints proximal to the metatarsophalangeal and metacarpophalangeal joints. Identification and

collection of TGCT cases was performed in the centres of origin and data were collected based on

the initial treatment at tertiary centres. Data were encrypted and transferred to the international

multicentre database at the Leiden University Medical Centre (LUMC). Patient accrual occurred

between May 2016 until May 2018.

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Figure 1 Intra-articular localized-TGCT in the posterior part of the left knee in a 19 year old female. a. Sagittal

T1-weighted Magnetic Resonance (MR) imaging after intravenous contrast injection with fat suppression. TGCT

shows marked enhancement after contrast injection. b. TGCT shows an intermediate to low signal intensity on

a sagittal T2-weighted MR scan. c. On a sagittal proton-density weighted MR imaging, localized-TGCT presents

with low signal intensity. d. Macroscopic aspect of a well-circumscribed localized-TGCT after complete open

resection. Arrow shows brownish areas, representing hemosiderin depositions. On the ruler, 1 block equals 1 cm.

a b

c d


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7

Study parameters

Collected patient-, tumour- and treatment characteristics with corresponding definitions are

shown in appendix table 1. Complete data on core criteria was necessary for reliable analyses. The

following characteristics were defined as core criteria: TGCT-type, admission status, date and type

of initial treatment at tertiary centre and first local recurrence.

Patient-, tumour- and treatment characteristics

Thirty-one specialized sarcoma centres spread throughout Europe, North America, Canada and Asia

collaborated to provide a total of 2169 TGCT cases. The present study focuses on localized-TGCT (table

1), therefore patients with diffuse-TGCT (N=1192) or unknown type TGCT (N=36) were excluded.

Statistical analyses

The endpoint for statistical analysis was local recurrence free survival after initial treatment in a tertiary

centre. Recurrent disease was defined as new disease presence after resection performed in a tertiary centre

or progressive residual disease (as diagnosed on repeated follow-up Magnetic Resonance (MR) imaging).

To investigate the effect of risk factors on outcome, univariate analyses were performed and

significant factors (p<0.05) were subsequently included in a multivariate analysis. Proposed

risk factors were admission status (therapy-naïve versus recurrent disease), sex (male versus

female), age (≤35 years versus >35 years), localization (knee versus hip versus foot and ankle

versus upper extremity), bone-involvement (present versus absent), surgical technique (open

versus arthroscopic) and size (<5 cm versus ≥5 cm). Patients with treatment ‘wait and see’ or

‘endoprosthetic reconstruction’ were excluded from statistical analyses (N=85).

Observed recurrence free survival probabilities at 3, 5, and 10 years were computed for all cases

and subgroups based on admission status and localization.

All data were selected for completeness on core criteria (appendix table 1 and figure 1). Statistical

analyses were carried out using R version 3.4.1. Exact survival information and statistical methods

are shown in supplementary material.

Purposefully, an estimate of the median time to recurrence was not provided. Calculating such

a median, based on patients for whom a recurrence was recorded, would assume that all other

patients could not experience a recurrence in the future. The extent of this so-called immortal time

bias is unknown. For this reason, such an estimate will always be an underestimation of the true

time to recurrence.

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Chapter seven

^Therapy-naïve or primary admission at tertiary centre are considered similar. ^^≥1 Surgery elsewhere

or recurrent admission are considered similar. *Digits are excluded. #Symptoms were defined as either

pain, swelling, stiffness or limited range of motion (table 8-9). $Wait and see or conservative treatment are

considered similar. +Endoprosthetic reconstruction or wait and see as initial treatment are excluded for

risk and survival analyses. &Resection not specified is considered either arthroscopic- or open resection.

Table 1 Patient-, tumour- and treatment characteristics

Characteristics Overall (%)

Total number 941 (100)

Admission status (N=941) Therapy naïve^

≥1 Surgery elsewhere^^897 (95)

44 (5)Sex (N=941) Male Female

360 (38)581 (62)

Median age at initial treatment years (N=882) IQR ≤35 years >35 years

3927-50

374 (42)508 (58)

Localization (N=941) (figure 2) Knee Hip Ankle Foot* Shoulder Elbow Wrist Hand* Other

633 (67)37 (4)

119 (13)58 (6)9 (1)

14 (2)24 (3)33 (4)14 (2)

Bone involvement (N=689) Present Absent

57 (8) 632 (92)

Median duration of symptoms# months (N=571) IQR

94-24

Type of (surgical) treatment at tertiary centre (N=930) Arthroscopic resection One-staged open resection Endoprosthetic reconstruction+

Wait and see$,+

Resection not specified&

140 (15)675 (73)

21 (2)64 (7)30 (3)

Median tumour size initial treatment in cm (N=637) IQR <5 cm ≥5 cm

3.02.0-4.5

496 (78)141 (22)

Adjuvant therapy initial treatment (N=787) External beam radiotherapy 90Yttrium Systemic targeted therapy Other None

8 (1)21 (3)2 (0.3)11 (1)

745 (95)


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7

Ethical consideration

This study is conducted according to the Declaration of Helsinki (October 2013) and approved by

the institutional review board (CME) from the Leiden University Medical Centre (LUMC) (May 4th,

2016; G16.015).

Source of Funding

The department of orthopaedics of the Leiden University Medical Centre (LUMC) receives research

funding by Daiichi Sankyo.

1%

2%

4%3%4%

67%

13%

6%

Figure 2 Skeleton showing localization of TGCT in 941 localized-

TGCT cases. 14 (2%) cases were classified as ‘other localization’.

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Chapter seven

results

Oncologic outcome

In 823 patients with localized-TGCT of large joints and complete survival data, 100 (12%) had a

recurrence during the follow-up period. Recurrence free survival (RFS) continued to decrease with

longer follow-up times (table 2-3, figure 3-5).

Univariate- and multivariate analyses for local recurrence

The risk factor admission status was highly associated with significant differences in recurrence risk

(p <0.001) in univariate analysis of 823 patients with localized-TGCT and complete core data: RFS at

5 years in patients entering the tertiary hospital with recurrent disease (surgery elsewhere) was 34%

(95% CI 17-51), compared with 86% (95% CI 82-89) in therapy naïve patients (figure 3). After excluding

patients initially treated elsewhere, the risk factors tumour size and surgical technique were found to

Table 2 Oncologic outcome after surgical treatment of localized-TGCT affecting large joints

Localized-TGCT

First local recurrence after initial treatment at a tertiary centre (N=823) Present Absent

100 (12%) 723 (88%)

Total number of recurrences (N=100) 1 2 ≥3

82 (82%)13 (13%)

5 (5%)

Mean total number of surgeries (N=657)Mean total number of surgeries in recurrent disease (N=100)

1.2 (range 1-5)2.1 (range 1-5)

Median follow-up months (N=823) 37 (95%CI 33-40)

Status last follow-up (N=743) No evidence of disease Alive with disease - wait and see Alive with disease - awaiting treatment Death of other disease Lost to follow-up*

569 (73%)29 (9%)6 (1%)

2 (0.1%)137 (17%)

*Lost to follow-up was defined as follow-up less than 6 months or stratified during follow-up as lost to follow-up


147

7be positively associated with first local recurrence (table 4-5, figure 3-5). Younger patients ≤35 years

also had fewer recurrences than older patients (82% vs 88%, p=0.04). Similar results were calculated

in a subgroup analysis in therapy naïve patients with localized-TGCT affecting the knee.

Observed recurrence free survival according to admission status and localization

As arthroscopic resection is less common in the hip, foot/ankle and upper extremity, arthroscopic

and open resection were compared for TGCT affecting the knee (figure 5). The highest recurrence

rates occurred in therapy naïve patients with tumours located within the knee joint who were

initially treated with an arthroscopic resection (18%) (figure 6).

When comparing therapy naïve patients with patients initially treated elsewhere, a declining RFS

was observed at 3, 5 and 10 years in subgroup analyses of patients with tumours located in the

knee, foot/ankle and upper extremity (table 6).

Complications

A total of 34 (4%) complications after surgical treatment of localized-TGCT were reported (table

7). The majority of these complications presented after open resection (30/34; 88%). Following

arthroscopic resection, two complications were reported (6%).

Functional outcome

Prior to surgical treatment, the majority of patients had symptoms of pain (73%) and swelling (66%)

(table 8). After surgical treatment, at final follow-up, symptoms of pain, swelling, joint stiffness and

limited range of motion were absent in the majority of cases.

Table 3 Localized-TGCT recurrence free survival (RFS) of all patients and therapy naïve patients treated at a tertiary centre

Year N all % RFS all (95%CI) N therapy naïve % RFS therapy naïve (95%CI)

3 388 88 (85-91) 372 90 (88-93)

5 231 83 (80-87) 223 86 (82-89)

10 66 79 (75-84) 63 82 (78-87)

N is number of patients at risk at 3, 5, and 10 years

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Chapter seven

Figure 3 Local recurrence free survival curve in localized-TGCT stratified for admission status (p<0.001)

Time zero was date of initial resection at tertiary centre. Primary: patient with therapy-naïve disease initially

treated at tertiary centre, recurrent: patient initially treated elsewhere

Years since surgery

Prob

abili

ty o

f RFS

primary 791 490 298 172 99 53

recurrent 32 14 10 8 5 1

years 0 2 4 6 8 10

number at risk

strata: primary recurrent


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7

Table 4 Univariate analyses in 791 patients with therapy naïve localized-TGCT

Variable N % RFS at 5 years 95%CI P value

Age

≤35 years 343 82 77-88 0.04

>35 years 447 88 84-92

Sex

male 292 88 82-93 0.56

female 499 85 80-89

Localization

knee 529 85 81-89 0.71

foot/ankle 156 84 76-93

upper extremity 82 90 81-98

Size

<5 cm 454 89 85-94 0.009

≥5 cm 124 76 66-87

Bone involvement

absent 543 85 81-89 0.70

present 50 74 57-91

Surgical technique

open 629 87 83-91 0.04

arthroscopic 132 80 72-88

RFS: Recurrence free survival, 95%CI: 95% Confidence interval

Table 5 Multivariate analyses in 554 patients with therapy naïve localized-TGCT

Variable Hazard ratio 95% CI P value

Age per year 0.99 0.97-1.01 0.425

Size <5 cm 1

≥5 cm 2.50 1.32-4.74 0.005

Surgical technique open 1

arthroscopic 2.18 0.98-4.84 0.056

95%CI: 95% Confidence interval

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Chapter seven

Years since surgery

<5 cm 454 267 149 91 58 36

≥5 cm 125 75 36 21 13 6

years 0 2 4 6 8 10

number at risk

strata: <5 cm ≥5 cm

Prob

abili

ty o

f RFS

Figure 4 Local recurrence free survival curve in therapy naïve patients with localized-TGCT stratified for size

(p=0.009). Time zero was date of initial resection at tertiary centre.

1.00

0.75

0.50

0.25

0.000 2 4 6 8 10


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7

Figure 5 Local recurrence free survival curve in patients with therapy naïve localized-TGCT affecting the knee

stratified for surgical technique (p=0.02). Time zero was date of initial resection at tertiary centre. Open: open

resection, arthroscopic: arthroscopic resection

Years since surgery

open 400 256 154 77 40 21

arthroscopic 114 70 52 35 22 9

years 0 2 4 6 8 10

number at risk

strata: open arthroscopic

Prob

abili

ty o

f RFS

1.00

0.75

0.50

0.25

0.000 2 4 6 8 10

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Chapter seven

For a mean of 501 (53%) patients with localized-TGCT, complete data were available both prior to

treatment and at last follow-up (table 9). The majority of patients experienced pain and swelling

prior to initial treatment, of which 71% and 85% were resolved after surgery at final follow-up.

Swelling or stiffness might coincide with recurrent disease as 34% (21/61) and 40% (8/20) of

patients with swelling and joint stiffness respectively at final follow-up had recurrent disease. In

contrast to pain, limited range of motion or chronic use of analgesics, as 20% (25/124), 30% (8/27)

and 29% (7/24), respectively, had recurrent disease.

Chronic analgesic treatment versus complications

Two of 26 patients (8%) with a complication used chronic analgesic treatment compared to five of

429 (3%) patients without a complication.

Figure 6 Flowchart localized-TGCT. Primary: patient was first seen at tertiary centre with therapy-naïve

disease, recurrent: patient initially treated elsewhere, AR: Arthroscopic resection, OR: Open resection, SR:

Surgical resection (either arthroscopic or open resection). Treatments other than surgical resections were not

included in this flowchart (e.g. endoprosthetic reconstruction, wait and see treatment or adjuvant therapy).

Upper extremity includes shoulder, elbow, wrist and hand. Other localization (N=14) were not included in this

flowchart.

897 primary

35 hip

164 ankle/foot

73 upper extremity

24 SR

155 SR

69 SR

0 recurrences

14 recurrences (9%)

7 recurrences (10%)

611 knee114 AR

400 OR

20 recurrences (18%)

34 recurrences (9%)

44 recurrent

941 localized-TGCT


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7

Table 6 Recurrence free survival (RFS) probabilities for localized-TGCT

Admissionstatus Localization N+ %RFS at

3 years 95% CI %RFS at 5 years 95% CI %RFS at

10 years 95% CI

primary knee 529 89 87-93 85 81-89 81 76-87

primary foot/ankle 156 90 84-96 84 76-93 81 71-91

primary upper extremity* 82 93 86-100 90 81-98 86 74-97

recurrent knee 16 44 19-68 44 19-68 **

recurrent foot/ankle 11 30 3-57 18 0-41 18 0-41

recurrent upper extremity* 3 67 13-100 67 13-100 67 13-100

Since the hip was affected sporadically (primary N=24; recurrent N=2) without recurrent disease during follow-up,

reliable analyses were not possible. +N: number at baseline (time point = 0), *Upper extremity including other localization,

**Survival estimates of recurrent knee patients at 10 years could not be estimated (due to lack of follow-up information).

Primary: patient was first seen at tertiary centre with therapy-naïve disease, recurrent: patient initially treated elsewhere,

95%CI: 95% Confidence interval.

Table 7 Complications after surgical treatment at tertiary centre (N=763)

Complications after surgical treatment N (%)

Superficial wound infection 11 (1)

Deep wound infection 1 (0.1)

Joint stiffness$ 5 (0.7)

Haemorrhage 1 (0.1)

Neurovascular damage 3 (0.4)

Thrombosis 3 (0.4)

Other+ 10 (1)

As osteoarthritis is either caused by extensive disease or by (multiple) treatments, this was not taken into account for

complications. $Joint stiffness requiring manipulation under anaesthesia. +Other surgical complications after initial

treatment included: joint subluxation (hip), compartment syndrome, ligament incision during surgery, complex

regional pain syndrome, tourniquet blistering, tendinitis.

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Chapter seven

Table 8 Symptoms prior to treatment and at final follow-up

Symptom Pre-treatment Final follow-up

Pain (PT 767, FF 522) 560 (73%) 128 (25%)

Swelling (PT 675, FF 525) 448 (66%) 64 (12%)

Joint stiffness (PT 663, FF 525) 65 (10%) 21 (4%)

Limited range of motion (PT 667, FF 523) 110 (16%) 27 (5%)

Chronic analgesic treatment* (FF 568) 25 (4%)

Presented numbers indicate presence of symptom. *Chronic analgesic treatment data were only collected at

final follow-up, PT: total number pre-treatment, FF: total number final follow-up

Table 9 Comparing symptoms localized-TGCT prior to treatment to last follow-up

No pain last fu Pain last fu Total

No pain initially 122 (24%) 18 (4%) 140

Pain initially 260 (52%) 104 (21%) 364

No swelling last fu Swelling last fu

No swelling initially 160 (32%) 11 (2%) 171

Swelling initially 284 (56%) 50 (10%) 334

No stiffness last fu Stiffness last fu

No stiffness initially 427 (86%) 16 (3%) 443

Stiffness initially 50 (10%) 4 (1%) 54

No limited range of motion last fu

Limited range of motion last fu

No limited range of motion initially 385 (77%) 16 (3%) 401

Limited range of motion initially 88 (18%) 9 (2%) 97

fu: follow-up.


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7

discussion

The results of this international multicentre study offer reliable insight into the outcome of the

treatment of patients with the orphan and heterogeneous disease localized-type Tenosynovial

Giant Cell Tumour (TGCT). We evaluated oncologic results, complications and functional results

after surgical treatment. The greatest strength of this dataset is that it represents the largest

collection of localized-TGCTs of large joints in the scientific literature, including a subgroup of

patients with long follow-up (>10 years).

Oncologic outcome

Surgical resection of TGCT has been the treatment of choice by either an arthroscopic or open

technique, based on the preference of the patient and treating physician, and might also differ by

centre. Physicians in favour of arthroscopic resection claim faster recovery, a lower complication

rate and less joint morbidity23-30. However, opponents of arthroscopic resection point out the risk

of inadequate excision, higher recurrence rates and a theoretical risk of joint seeding and portal

contamination13, 16.

In the current study, we identified higher recurrence rates after arthroscopic (18%) compares to

open resection (9%) of therapy naïve localized-TGCT affecting the knee joint. This is also presented

in the systematic review of van der Heijden et al. (6% after arthroscopic and 4% after open

resection)13. These higher recurrence rates may be explained by the longer follow-up times on

average and the larger sample size of localized-TGCT cases (table 4-5, figure 3-5). The single most

important and significant risk factor for local recurrence is recurrent disease at presentation. In a

subgroup analysis of patients with primary disease treated in a tertiary centre, the greatest risk for

first local recurrence was associated with tumour size ≥5 cm and arthroscopic resection at initial

treatment. This could be attributed to the fact that arthroscopic en bloc and complete resection

is likely only possible in a small percentage of cases with small/pedunculated and accessible

lesions, whereas in most cases intralesional removal would be performed arthroscopically thereby

potentially leaving residual disease in the joint. Several other studies reported higher rates of

recurrences after incomplete resections10, 23, 31, 32.

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Chapter seven

Complications

All surgical treatments are associated with complications and data following resection of TGCT are

currently lacking in recent literature. The present study reported a complication rate of 4% after

surgical treatment for localized-TGCT. The most common complication in localized-TGCT was a

superficial wound infection after open resection.

Functional outcome

TGCT related symptoms are mainly joint pain, swelling, stiffness and limited range of motion, but

these occur with great variability in extent and severity. Gelhorn et al. concluded that not all patients

experience all symptoms to the same extent (e.g. swelling but no pain, or pain and swelling but no

stiffness or limited range of motion)9. Symptoms prior to initial treatment at a tertiary centre were

compared with symptoms at last follow-up. Initial symptoms of pain and swelling improved after

surgical treatment(s) in 71-85% of patients. This is comparable with a crowdsourcing study in 337

TGCT patients originating from 30 countries8. Stiffness and limited range of motion seemed not

to be debilitating symptoms in the majority of patients, either initially or at last follow-up. There

was no relationship between symptoms at last follow-up and recurrent disease. Symptoms are

subjective for each patient and not all patients were included with complete data. Nevertheless,

the main initial TGCT-related complaints are pain and swelling and these could potentially improve

after surgical treatment(s).

Joint specific analyses

In daily practise, TGCT patients present as a heterogeneous group. To provide reliable results,

homogeneous subgroup analyses are essential. This was possible with our individual participant

data meta-analysis. Even though quite a large number of TGCT cases were collected, complete risk

factor subgroup analyses were only feasible for TGCT affecting the knee (67%).

Limitations

As a result of increased awareness about TGCT, more patients are now being referred to (tertiary)

orthopaedic oncological referral centres as new targeted therapies are being examined in on-

going RCTs33-35. However, data on patients treated at non-specialized centres are lacking in both

the literature and within the present study. Therewith, selection (referral) bias is induced. The


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7

degree of selection bias according to affected joints is negligible, as similar percentages of affected

localizations (figure 2) were reported in a recent incidence calculation study with nationwide

coverage6. Non-specialized centres that resect smaller tumours without local recurrence were not

present, possibly introducing an overestimation of LR for localized-TGCT in general.

As data were collected by local investigators or physicians according to the multicentre study

design, data quality depended on data registry on site. Only data available in the source data file

of the patients could be retrieved. In addition, interpretation of individual parameters could differ.

No central histopathological review was performed, as it was assumed that each centre provided

the correct diagnosis as set by their histopathology department.

Recurrence rates could either be over-estimated or under-estimated. Over-estimation since

date of a second operation or follow-up status ‘alive with disease’ was classified as recurrence

(if recurrence data was missing). On the contrary, under-estimation could be present if patients

with recurrent disease did not return at all or did not return to their original centre. It should

be noted that patients with recurrent disease had a longer follow-up compared with patients

without recurrent disease. This could be explained by the fact that patients without symptoms

and (assumed) without recurrent disease were dismissed from follow-up and therefore presented

with shorter follow-up times. Plausibly, patients without symptoms are not experiencing recurrent

disease. In addition, if treatments were recently performed, patients also had shorter follow-up

times and are still at risk of recurrence.

conclusion

We present the largest international study that evaluated the clinical profile, management and

outcome for patients with TGCT. Localized-TGCT remains a heterogeneous and orphan disease,

with an overall recurrence free survival of 83% at 5 years. Risk factors for recurrent disease were

larger tumours, primary treatment with arthroscopy and initial surgical treatment outside of a

tertiary centre. Relatively low complication rates and good functional outcomes warrant complete

resection, most commonly accomplished by an open surgical approach, to reduce recurrence

rates in high risk patients.

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Chapter seven

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conference. 2018.







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Chapter seven

appendix

Table 1 Collected patient and tumour characteristics with corresponding definitions.

Characteristic Definition

TGCT-type Localized-/diffuse-TGCT as defined by the 2013 WHO1, 2

Admission status Previously treated*

Sex Male/female

Age at initial treatment Age at initial treatment

Side Left/right

Localization TGCT affected joint

Bone involvement Discontinuation of cortex by tumour ingrowth*

Date first diagnosis Date first diagnosis

Duration of symptoms Duration of symptoms in months

Pain, swelling, stiffness and limited range of motion prior to initial treatment and at last follow-up

(Clinically relevant) Pain, swelling, stiffness+ and limited range of motion prior to initial treatment* and at last follow-up

Total number surgeries All surgeries related to TGCT, including re-operations for complications

Date initial treatment** Date initial treatment at tertiary centre and date(s) of consecutive treat-ment(s)

Initial treatment**Type of initial treatment and consecutive treatment(s): arthroscopic re-section, one-staged open resection, two-staged open resection, (tumour)prosthesis, amputation, wait and see++, synovectomy not specified

Tumour size Largest size in any dimension (cm), according to the 2013 WHO classifica-tion1, 2, <5 and ≥5 cm were compared

Adjuvant therapy Nothing, radiotherapy, 90Yttrium, targeted therapy, cryosurgery, other

Date complication Date complication related to surgical treatment

Complication Type of complication related to surgical treatment: no complication, super-ficial wound infection, deep wound infection, joint stiffness+, haemorrhage, neurovascular damage, thrombosis, other, unknown

Total number recurrences Total number local recurrences

Date final follow-up Date final follow-up

Status last follow-upNo evidence of disease, alive with disease wait and see, alive with disease planned surgery of adjuvant therapy, death of disease, death of other dis-ease, lost (<6 months follow-up)

Chronic analgesic treat-ment at last follow-up Chronic analgesic treatment at last follow-up

Characteristics in bold were core criteria. *These parameters were answered by present or absent. **(Date) initial treatment, initial treatment in tertiary centre is not necessarily first treatment of the patient. +Stiffness requiring manipulation under anaesthesia. ++Wait and see and conservative treatment are considered similar.


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7

Figure 1 Proportion of data missing per variable in localized-TGCT (N=941).

Symptoms prior to initial treatment at tertiary centre include pain, swelling, stiffness and limited range of

motion. Symptoms at last follow-up include pain, swelling, stiffness, limited range of motion and chronic

analgesic treatment at last follow-up.

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Chapter seven

Supplementary material participating international sarcoma reference centres

1. Leiden University Medical Center, Leiden, The Netherlands

2. Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

3. IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

4. Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

5. Istituto Ortopedico Gaetano Pini, Milano, Italy

6. Mount Sinai School of Medicine, New York, USA

7. Medical University Graz, Graz, Austria

8. Halen İstanbul Üniversitesi, Istanbul, Turkey

9. AOU Città della Salute e della Scienza, Torino, Italy

10. Orthopedic Hospital Gersthof, Vienna, Austria

11. Careggi University-Hospital, Firenze, Italy

12. University Medical Center Groningen, Groningen, The Netherlands

13. Academic Medical Center, Amsterdam, The Netherlands

14. Mount Sinai Hospital, Toronto, Canada

15. Beijing Jishuitan Hospital, Beijing, 100035, China

16. Institut Roi Albert II, Brussels, Belgium

17. Royal National Orthopedic Hospital, London, the United Kingdom

18. Hospital de Navarra, Pamplona, Spain

19. Centre hospitalier universitaire de Nantes, Nantes, France

20. Ludwig-Maximilians-University Munich, Munich, Germany

21. Medical University of Innsbruck, Innsbruck, Austria

22. Massachusetts General Hospital Harvard, Boston, United States of America

23. Chiba Cancer Center, Chiba, Japan

24. National Cancer Center, Tokyo, Japan

25. Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

26. Sytenko Institute of Spine and Joint Pathology, Kharkiv, Ukraine

27. Universitätsklinikum Jena, Jena, Germany

28. University of the Phil-Phil General Hospital, Manila, Philippines

29. Catholic University of Korea, Seoul, Korea

30. Cairo University, Cairo, Egypt

31. Wilhelmsburger Krankenhaus Groß Sand, Hamburg, Germany


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7

Supplementary material exact survival information and statistical methods

For some cases exact survival information was not available (appendix figure 1). In 7 out of 61 cases,

we could recover the missing recurrence indicator: in 2 cases patients had a second treatment and

in 5 cases patients had follow-up status ‘alive with disease’ and were classified as recurrent disease.

If the exact time of recurrence was not recorded, an approximation was sometimes possible. If

the date of surgery to treat a local recurrence was known, this was used instead (N=33). If this

information was missing as well, then the date of last recurrence was used as an upper bound

(N=5). Otherwise the date of last recorded follow-up was used as an upper bound (N=69). If data

on recurrence status or date of recurrence was missing and could not be recovered as described,

patients were excluded for risk- and survival analyses (N=64).

Some centres did not record follow-up time in patients without recurrent disease. To prevent

exclusion of these patients, we imputed their follow-up time (N=97). Multiple imputation

technique was applied and 5 complete data sets were imputed using the R-package Amelia II18.

Statistical analyses were conducted on all data sets and the results were then pooled following

Rubin’s rule19.

As a consequence of the approximation of the time of recurrence by upper bounds in some cases,

common survival methods (Kaplan-Meier estimate, log rank test) were substituted by methods

that allow interval censoring. Observed survival curves and probabilities were computed using

non-parametric maximum likelihood estimates for interval censored data with the R-package

interval20. P-values for the univariate analyses were calculated with the score test of Sun (1996)21.

Covariates that were found to have a significant association with local recurrence free survival in

the univariate analysis were included in a multivariate Cox regression analysis using the icenReg

R-package, which allows for interval censored data22.

diF

Fuse

outcome of surgical treatment

for patients with diffuse-type


chap

ter

eigh

t

largest cohort of individual participant data meta-analysis of 31 international sarcoma centres

M.J.L. Mastboom1, E. Palmerini2, F.G.M. Verspoor3, A.J. Rueten-Budde4, S. Stacchiotti5, E.L. Staals6,

G.R. Schaap7, P.C. Jutte8, W. Aston9, H. Gelderblom10, A. Leithner11, D. Dammerer12, A. Takeuchi13, Q. Thio14, X. Niu15,

J.S. Wunder16, TGCT-study group*, M.A.J. van de Sande1

Submitted.

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Chapter eight

1 Orthopaedic Surgery, Leiden University Medical Center, Leiden, the Netherlands

2 Medical Oncology, Musculoskeletal Oncology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

3 Orthopaedic Surgery, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

4 Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands

5 Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

6 Orthopaedic Surgery, Musculoskeletal Oncology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

7 Orthopaedic Surgery, Academic Medical Center, Amsterdam, the Netherlands

8 Department of Orthopaedics, University Medical Center, University of Groningen, Groningen, the Netherlands

9 Orthopedic surgery, Royal National Orthopedic Hospital, London, the United Kingdom

10 Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands

11 Department of Orthopaedic Surgery, Medical University Graz, Graz, Austria

12 Orthopedic surgery, Medical University of Innsbruck, Innsbruck, Austria

13 Orthopaedic surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

14 Orthopedic surgery, Massachusetts General Hospital Harvard, Boston, United States of America

15 Department of Orthopedic Oncology, Beijing Jishuitan Hospital, Beijing, 100035, China

16 University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Canada

*TGCT study-group

M. Fiocco, P.D.S. Dijkstra, R.J.P. van der Wal, P.A. Daolio, P. Picci, A. Gronchi, S. Ferrari, H. Özger, R.G. Maki, H.W.B.

Schreuder, I.C.M. van der Geest, J.A.M. Bramer, M. Boffano, E. Goldenitsch, D. Campanacci, P. Cuomo, P.C.

Ferguson, A.M. Griffin, Y. Sun, T. Schubert, K. Patel, M.S.J. Aranguren, A. Blancheton, F. Gouin, H.R. Dürr, C.F.

Capellen, J. Schwab, S. Iwata, O. Vyrva, W. Weschenfelder, E.H.M. Wang, M. Wook Joo, Y.K. Kang, Y.G. Chung, W.

Ebeid, J. Bruns, T. Ueda

Diffuse-type tenosynovial giant cell tumours

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8

abstract

Objective

Diffuse-type Tenosynovial Giant Cell Tumour (TGCT) is a rare, locally aggressive and difficult to treat

disease. An international multicentre-pooled retrospective study of individual patient data was developed

to describe global treatment protocols, evaluate oncological outcome, complications and functional

results. A secondary study aim was to identify risk factors for local recurrence after surgical treatment.

Methods

Patients treated in 31 sarcoma reference centres between 1990 and 2017, with histologically proven diffuse-

TGCT of large joints were included. Of 1192 cases of diffuse-TGCT, 58% were female with a median age

35 years. 64% affected the knee and in 54% primary treatment was one-staged open synovectomy. Risk

factors were tested in a univariate analysis and significant factors subsequently included for multivariate

analysis, with first local recurrence after surgical treatment in a tertiary centre as the primary outcome.

Results

At a median follow-up of 54 (95%CI 50-58) months, recurrent disease developed in 44% of all

surgically treated cases, with local recurrence free survival (RFS) at 3, 5, 10 years of 62%, 55%

and 40%, respectively. The strongest risk factor for recurrent disease was prior recurrence (HR

3.5 95%CI 2.8-4.4, p<0.001) with a 5-year RFS of 64% in surgery naïve patients compared with

25% in patients operated for recurrent disease. Complications were noted in 12% of patients. Pain

and swelling improved after surgical treatment(s) in 59% and 72% of patients respectively. In a

subgroup analysis including only naïve cases affecting the knee, neither sex (male;female), age

(≤35years;>35years), bone-involvement (present;absent), surgical technique (open;arthroscopic)

nor tumour size (<5cm;≥5cm) yielded an association with the first local recurrence.

Conclusion

This largest international individual data study of patients with diffuse-TGCT, provides a comprehensive

and up to date disease overview, evaluating the clinical profile and management of the disease. Since

complete resection of diffuse-TGCT could be regarded as nearly impossible and recurrence rates are

unacceptably high after both arthroscopy and open synovectomy in the knee, even in specialized

centres, a multimodality approach in this disease, including adjuvant treatments, is warranted.

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Chapter eight

introduction

In the most recent WHO classification (2013), giant cell tumour of the tendon sheath and

pigmented villonodular synovitis (PVNS) were unified by one overarching term: tenosynovial

giant cell tumours (TGCT). This rare, mono-articular disease arises from the synovial lining of

joints, bursae or tendon sheaths in predominantly young adults1, 2. Excluding digits, TGCT is most

commonly diagnosed around the knee and can be found in other weight bearing joints as well1-4.

Two clinically and radiographically distinct subtypes of TGCT are defined with different natural

courses of disease. The localized-type is defined as a well-circumscribed nodule. On the contrary,

the diffuse-type is known as an ill-circumscribed, locally aggressive and invasive tumour (figure 1,

chapter 1, page 13)1, 2, 5. Even though histopathology and genetics seem identical, the biological

behaviour of both subtypes is incomparable and therefore necessitates separate evaluations,

analyses and treatments. The current study focuses on diffuse-TGCT of large joints.

Macroscopically, diffuse-type TGCT involves a large part or even the complete synovial lining of

a joint with either a typical villous pattern (intra-articular) or a multi-nodular appearance (extra-

articular), including a diverse colour pattern, varying from white-yellow to brown-red areas. This

subtype shows an infiltrative growth pattern. Definite diagnosis is established on microscopy by

an admixture of mononuclear cells (histiocyte-like and larger cells) and multinucleated giant cells,

lipid-laden foamy macrophages (also known as xanthoma cells), siderophages (macrophages

including hemosiderin-depositions), stroma with lymphocytic infiltrate and some degree of

collagenisation. Molecular analysis is generally not required to confirm the diagnosis.

Pain, (haemorrhagic) joint effusion, stiffness and limited range of motion are the main

clinical complaints6. These non-specific symptoms frequently cause a delay in diagnosis7. The

predominant standard of care is surgical resection of diffuse-TGCT, either arthroscopically or

with an open resection or a combination of both, in order to: (1) reduce debilitating symptoms

and joint destruction caused by the disease process; (2) improve limb function; and (3) minimize

the risk of local recurrence. Clinical and oncological outcomes following surgery largely depend

on multiple factors including preoperative diagnostic evaluation, the localization and extent of

disease and possibly the choice of treatment modalities by orthopaedic surgeons3, 5, 8-10. Diffuse-


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8

TGCT frequently causes significant morbidity due to the invasiveness of the surgical resection

and the high rate of local recurrence (14-40% depending on surgical procedure and follow-up

time), with deteriorated health-related quality of life6, 8, 9, 11-14. Therefore, treatment of diffuse-TGCT

may include adjuvant or multimodality treatment such as external beam radiation therapy10, 15, 16,

radiation synovectomy with 90Yttrium17 or CSF1 inhibitors, such as nilotinib, imatinib, pexidartinib,

emactuzumab, cabrilazimab and MSC11018-22. Of note, so far none of these agents have been

formally approved for use in the disease, and long-term efficacy is unknown.

The incidence of diffuse-TGCT of large joints is 4.1 per million person-years4. Therefore, the current

literature mainly consists of relatively small, or larger but heterogeneous case-series. Risk-factors for

recurrent disease in individual patients need to be identified by evaluating outcomes of different

treatment strategies. Since (larger) randomized controlled trials on the role of surgery in TGCT are

lacking, individual participant data meta-analysis is currently the highest achievable evidence. It

offers advantages above a meta-analyses, including: (1) missing data can be accounted for at an

individual patient level, (2) subgroup analyses can be performed (e.g. per affected joint) and (3)

follow-up information can be updated23. Therefore, we aimed to collaborate with tertiary sarcoma

centres across the globe to include individual patient data in this investigation.

The main aim of this international multicentre cohort study is to provide comprehensive and

up to date insights on the surgical treatment and outcome for patients with diffuse-type TGCT.

Oncologic results, complications and functional results are described. In addition, risk factors for

local recurrence after surgical treatment are identified.

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Chapter eight

methods

Recruitment and patient inclusion criteria

Patients of any age treated between January 1990 and December 2017 in one of 31 international

sarcoma centres (supplementary material: participating international sarcoma reference centres,

page 160) with histologically proven TGCT of large joints were retrospectively included. Large

joints were defined as all joints proximal to the metatarsophalangeal and metacarpophalangeal

joints. Identification and collection of the patients was performed in the centres of origin and data

were analysed from initial treatment at these tertiary centres. Data were encrypted and transferred

to the international multicentre database at the Leiden University Medical Centre (LUMC), with

patient collection ending as of May 2018.

Study parameters

Collected patient-, tumour- and treatment characteristics with corresponding definitions are

shown in appendix table 1 (chapter 7, page 158). The following characteristics were defined as

core criteria: TGCT-type (localized-; diffuse-; unknown-type), admission status (therapy-naïve; 1st

recurrence; 2nd recurrence; 3rd recurrence; etc.) date and type of initial treatment at a tertiary centre

(arthroscopic synovectomy; one-staged synovectomy; two-staged synovectomy; synovectomy

not specified; (tumour)prosthesis; amputation; wait and see); and first local recurrence after

treatment (yes; no) in a tertiary centre. Complete data on these core criteria were necessary for

reliable analyses.

Patient-, tumour- and treatment characteristics

Thirty-one specialized sarcoma centres spread throughout Europe, North America, Canada and

Asia collaborated to provide a total of 1192 diffuse-TGCT cases (table 1). As per entry criteria,

patients with localized-TGCT (N=941) and unknown type TGCT (N=36) were excluded.

Statistical analyses

The primary endpoint was local recurrence free survival (RFS) after initial treatment in a tertiary

centre. Recurrent disease was defined as the presence of new disease after resection (and

synovectomy) performed in a tertiary centre or progressive residual disease (as diagnosed by local

investigators on repeated follow-up Magnetic Resonance (MR) imaging).


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Table 1 Patient-, tumour- and treatment characteristics


Total number 1192 (100)

Admission status (N=1192) Therapy naïve^

≥1 Surgery elsewhere^^910 (76)282 (24)

Sex (N=1192) Male Female

499 (42)693 (58)

Median age at initial treatment years (N=1122) IQR

3526-48

Localization (N=1192) Knee Hip Ankle Foot* Shoulder Elbow Wrist Hand* Other

758 (64)124 (10)162 (14)

63 (5)15 (1)17 (1)25 (2)13 (1)15 (1)

Bone involvement (N=847) Present Absent

259 (30) 588 (70)

Median duration of symptoms# months (N=744) IQR

186-36

Type of surgical treatment at tertiary centre (N=1163) Arthroscopic synovectomy One-staged open synovectomy Two -staged open synovectomy##

(Tumour)prosthesis+,¥

Amputation¥

Wait and see$,¥

Synovectomy not specified

159 (14)628 (54)187 (16)

63 (5)3 (0.3)76 (7)47 (4)

Median tumour size initial treatment in cm (N=701) IQR <5 cm ≥5 cm

5.43.0-8.8

297 (42)404 (58)

Adjuvant therapy initial treatment (N=1033) External beam radiotherapy 90Yttrium Systemic/molecular targeted treatment Other None

58 (6)60 (6)15 (1)11 (1)

889 (86)

IQR, Interquartile Range; ^Therapy-naïve or primary admission status at tertiary centre are considered similar; ^^≥1 Surgery elsewhere or recurrent admission status are considered similar; *Digits are excluded; #Symptoms were defined as either pain, swelling, stiffness or limited range of motion (table 7-8); ##A two-stage synovectomy is defined as two synovectomies within six months; +An arthrodesis is classified as (tumour)prosthesis; $Wait and see and conservative treatment are considered similar; ¥(Tumour)prosthesis, amputation or wait and see as initial treatment are excluded for risk and survival analyses.

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Chapter eight

To investigate the effect of risk factors on the outcome, univariate analyses were performed and

significant factors (p<0.05) were subsequently included into a multivariate analysis. Proposed risk

factors were admission status (therapy-naïve versus recurrent disease), sex (male versus female), age

(≤35 years versus >35 years), localization (knee versus hip versus foot/ankle versus upper extremity),

bone-involvement (present versus absent), surgical technique (open versus arthroscopic) and

tumour size (<5 cm versus ≥5cm). Patients with a wait and see policy or as initial treatment (tumour)

prosthesis surgery or an amputation were excluded from statistical analysis (N=142).

Observed RFS probabilities at 3, 5, and 10 years were computed for all cases and subgroups based

on admission status and localization.

Figure 2 Skeleton showing localization of TGCT

in 1192 diffuse-TGCT cases. 15 diffuse-TGCT cases

were classified as ‘other localization’

1%

1%

10%2%1%

64%

14%

5%


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8

For some patients exact survival information was not available (appendix: proportion of data

missing per variable). In 34 out of 107 cases, we could recover the missing recurrence indicator:

9 patients had a second treatment and 25 patients had follow-up status ‘alive with disease’ and

were classified as having recurrent disease. When the exact time of recurrence was not recorded,

an approximation was applied where possible. When the date of surgery to treat a recurrence was

known, this was used as the date of local recurrence instead (N=177). When this information was

missing as well, the date of last recurrence was used as an upper bound (N=58). Otherwise the

date of last recorded follow-up was used as an upper bound (N=69). When data on recurrence

status or date of recurrence was missing and could not be recovered as described, patients were

excluded for risk- and survival analyses (N=84).

Some centres did not record follow-up time for patients without recurrent disease. To prevent

exclusion of these patients, we imputed their follow-up time (N=79). Multiple imputation technique

was applied and 5 complete data sets were imputed using the R-package Amelia II24. Statistical

analyses were conducted on all data sets and the results were then pooled following Rubin’s rule25.

As a consequence of the approximation of the time of recurrent disease by upper bounds in some

cases, common survival methods (Kaplan-Meier estimate, logrank test) were substituted by methods

that allow for interval censoring. Observed survival curves and probabilities were computed using

non-parametric maximum likelihood estimates for interval censored data with the R-package

interval26. P-values for the univariate analyses were calculated with the score test of Sun (1996)27.

Covariates that were found to have a significant association with local recurrence free survival in

the univariate analysis were included in a multivariate Cox regression analysis using the icenReg

R-package, which allows for interval censored data28.

All data were selected for completeness on core criteria (appendix, chapter 7, page 158). Statistical

analyses were carried out using R version 3.4.1.

On purpose, an estimate of the median time to recurrence was not provided. Calculating such a

median based on patients for whom a recurrence was recorded, would assume that all other patients

could not experience a recurrence in the future. The extent of this so-called immortal time bias is

unknown. For this reason, such an estimate will be an underestimation of the true time to recurrence.

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Chapter eight

Ethical consideration

This study is conducted according to the Declaration of Helsinki (October 2013) and approved by the

institutional review board (CME) from the Leiden University Medical Center (LUMC) (May 4th, 2016; G16.015).

results

Oncologic outcome

In 966 patients with surgically treated diffuse-TGCT and complete survival data, 425 (44%) had a

tumour recurrence following treatment. The recurrence free survival (RFS) continued to decrease

with longer follow-up times (table 2-3, figure 3).

Univariate- and multivariate analyses for local recurrence

In univariate analysis of 966 patients with surgically treated diffuse-TGCT and complete core data,

the risk factor admission status was found to be significantly associated with recurrence: 5-year

RFS was 64% for therapy naïve patients (95% CI 60-68) compared to 25% for patients entering the

tertiary hospital with recurrent disease (95% CI 19-31; p <0.001). This difference was confirmed by

multivariate analysis (HR 3.5 95% CI 2.8-4.4, p<0.001).

After excluding patients admitted with recurrent disease, surgical technique was also positively

associated with first local recurrence (table 4). This result was confirmed by cox regression analysis

(HR 1.407; 95% CI 1.02-1.95, p=0.04). In a subgroup analysis of therapy naïve patients with diffuse-

TGCT affecting the knee, surgical technique was not found to be associated with first local

recurrence (p=0.113).

Observed recurrence free survival according to admission status and localization

Highest recurrence rates are report in TGCT affecting the knee; 43% after arthroscopic synovectomy

and 37% after open synovectomy (figure 4). A progressively declining RFS was seen at 3, 5 and 10

years in a subgroup analysis of the knee, hip, foot/ankle and upper extremity locations in patients

either admitted with therapy naïve TGCT or patients admitted with recurrent TGCT (table 5). After

10 years follow-up, patients with therapy naïve disease affecting the knee were found to have

the lowest RFS rates of all sites (46%, 95% CI 39-54). All patients entering a tertiary hospital with

recurrent disease exhibited very low RFS at 10 years (figure 3a).


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Table 2 Oncologic outcome after surgical treatment of diffuse-TGCT of large joints of all patients

primary treated at a tertiary centre


First local recurrence after initial treatment at tertiary centre (N=966) Present Absent

425 (44)541 (56)

Total number of recurrences (N=425) 1 2 ≥3

267 (63)85 (20)73 (17)

Mean total number of surgeries (N=707)Mean total number of surgeries in recurrent disease (N=425)

2.0 (range 1-10)2.7 (1-10)

Median follow-up months (N=966) 95% CI

54 50-58

Status last follow-up (N=891) No evidence of disease Alive with disease - wait and see Alive with disease - awaiting treatment Death of other disease Lost to follow-up*

587 (66)190 (21)

31 (3)10 (1)73 (8)

*Lost to follow-up was defined as follow-up less than 6 months or stratified during follow-up as lost to follow-up.

Table 3 Diffuse-TGCT recurrence free survival (RFS) all patients versus therapy naïve patients

treated at tertiary centre

Year N all % RFS all (95%CI) N therapy naïve % RFS therapy naïve (95%CI)

3 474 62 (59-65) 372 70 (67-74)

5 297 55 (51-58) 227 64 (60-68)

10 89 40 (35-45) 70 50 (44-56)

N is number of patients at risk for recurrent disease at 3, 5 and 10 years.

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Chapter eight

Years since surgery

Prob

abili

ty o

f RFS

primary 758 506 310 170 97 63

recurrent 208 128 88 53 30 18

years 0 2 4 6 8 10

number at risk

strata: primary recurrent

Figure 3a Local recurrence free survival curve in diffuse-TGCT stratified for admission status (p<0.001).

Time zero was date of initial resection at tertiary centre. Primary: patient with therapy-naïve disease initially

treated at tertiary centre, recurrent: patient initially treated elsewhere.

1.00

0.75

0.50

0.25

0.000 2 4 6 8 10


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Figure 3b Local recurrence free survival curve in patients with therapy naïve diffuse-TGCT affecting the knee

stratified for surgical technique (p=0.11). Time zero was date of initial resection at tertiary centre. Open: open

resection, arthroscopic: arthroscopic resection.

Years since surgery

open 346 225 146 71 39 29

arthroscopic 99 65 40 25 13 8

years 0 2 4 6 8 10

number at risk

strata: open arthroscopic

Prob

abili

ty o

f RFS

1.00

0.75

0.50

0.25

0.000 2 4 6 8 10

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Chapter eight

Figure 4 Flowchart of diffuse-TGCT patients with treatments and recurrences for each affected joint.

Primary: patient was first seen at tertiary centre with therapy-naïve disease, recurrent: patient initially treated

elsewhere, AS: Arthroscopic synovectomy, OS: Open synovectomy. Treatments other than AS and OS were not

included in this flowchart (e.g. (tumour)prosthesis, amputation, wait and see treatment).

910 primary

96 AS

358 OS



282 recurrent

1192 diffuse-TGCT

3 AS

64 OS

1 recurrence (33%)


9 AS

135 OS

3 recurrences (33%)


4 AS

42 OS

3 recurrences (75%)


105 hip

127 ankle/foot

55 upper extremity

559 knee

Complications

A total of 105 (12%) complications occurred following surgical treatment of diffuse-TGCT (table

6). The majority of these complications developed after one- or two-staged open synovectomy

(86/105; 82%). In comparison, 12 complications (11%) were reported following arthroscopic

synovectomy.

Functional outcome

Prior to surgical treatment, the majority of patients had symptoms of pain (76%) and swelling

(75%) (table 7). After surgical treatment, at final follow-up, these symptoms largely disappeared,

although 37% and 24% of patients respectively were still symptomatic. Joint stiffness and limited

range of motion were only present in 21% and 27% of cases, respectively, and these symptoms

improved slightly after treatment (17% and 19% at final follow-up).


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Table 4 Univariate analyses in 758 patients with therapy naïve diffuse-TGCT

Variable N %RFS at 5 years 95%CI P value

Age

≤35 years 391 64 59-70 0.94

>35 years 364 63 57-69

Sex

male 307 63 56-69 0.86

female 451 64 59-70

Localization

knee 471 61 56-66 0.10

hip 70 65 54-77

foot/ankle 158 72 64-81

upper extremity 59 59 44-74

Size

<5 cm 217 71 64-78 0.42

≥5 cm 295 64 58-71

Bone involvement

present 158 61 52-69 0.82

absent 425 64 58-69

Surgical technique

open 595 66 61-70 0.03

arthroscopic 120 54 44-64

A mean of 578 (48%) patients with diffuse-TGCT had complete data on symptoms both prior to

initial treatment and at final follow-up (table 8). The majority of patients experienced pain and

swelling prior to initial treatment, of which 59% and 72% resolved after surgical treatment(s).

Patients with initial complaints of stiffness and limited range of motion also improved after surgery

(64% and 73%).

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Chapter eight

Table 6 Complications after surgical treatment at tertiary centre (N=906)

Complications after surgical treatment N (%)

Superficial wound infection 15 (2)

Deep wound infection 10 (1)

Joint stiffness 32 (4)

Haemorrhage 7 (1)

Neurovascular damage 15 (2)

Thrombosis 1 (0.1)

Other+ 25 (3)

+Other surgical complications after initial treatment included: joint luxation (hip), compartment syndrome, ligament incision during surgery, complex regional pain syndrome, tourniquet blistering, tendinitis. As osteoarthritis is either caused by extensive disease or by (multiple) treatments, it was not taken into account for complications.

Table 5 Recurrence free survival probabilities at 3, 5, and 10 years for on type of TGCT, admission

status and localization

Admissionstatus Localization N+ % RFS at

3 years 95% CI % RFS at 5 years 95% CI % RFS at

10 years 95% CI

primary knee 471 68 63-73 61 56-66 46 39-54

primary hip 70 67 56-79 65 53-77 54 38-70

primary foot/ankle 158 79 72-87 72 64-81 57 44-70

primary upper extremity* 59 69 56-82 59 44-75 55 38-71

recurrent knee 145 29 21-36 25 18-32 15 8-21

recurrent hip 8 40 6-74 40 6-74 **

recurrent foot/ankle 39 43 27-59 24 10-38 18 4-33

recurrent upper extremity* 16 25 3-47 25 3-47 15 0-33

+N: number at baseline (time point = 0), *Upper extremity including other localization, **10 years RFS and associated 95%CI of recurrent hip cases could not be estimated (due to lack of follow-up information). Primary: patient was first seen at tertiary centre with therapy-naïve disease Recurrent: patient initially treated elsewhere, 95%CI: 95% Confidence interval.


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8

Table 7 Symptoms prior to treatment and at final follow-up

Symptom Pre-treatment Final follow-up

Pain (PT 969, FF 630) 738 (76%) 233 (37%)

Swelling (PT 775, FF 627) 579 (75%) 149 (24%)

Joint stiffness (PT 759, FF 617) 161 (21%) 105 (17%)

Limited range of motion (PT 760, FF 624) 209 (27%) 118 (19%)

Chronic analgesic treatment* (FF 714) 92 (13%)

*Chronic analgesic treatment data was only available at final follow-up; PT, pre-treatment; FF, final follow-up

Table 8 Comparing symptoms diffuse-TGCT prior to treatment to last follow-up

No pain last fu Pain last fu Total

No pain initially 118 (20%) 36 (6%) 154

Pain initially 255 (43%) 179 (31%) 434

No swelling last fu Swelling last fu

No swelling initially 119 (20%) 13 (2%) 132

Swelling initially 328 (56%) 125 (22%) 453

No stiffness last fu Stiffness last fu

No stiffness initially 383 (68%) 55 (10%) 438

Stiffness initially 82 (14%) 47 (8%) 129

No limited range of motion last fu

Limited range of motion last fu

No limited range of motion initially 337 (59%) 59 (10%) 396

Limited range of motion initially 128 (23%) 48 (8%) 176

Fu; follow-up

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Chapter eight

Local recurrence versus symptoms final follow-up

A higher percentage of patients with pain, swelling, stiffness and limited range of motion at final

follow-up had recurrent disease (pain; 55% recurrence versus 45% no recurrence, swelling; 66%

versus 34%, stiffness; 51% versus 49%, limited range of motion; 56% versus 44%).

More patients with recurrent disease 21% (64/300) used chronic analgesic treatment at last follow-

up compared to patients 6% (24/388) without recurrent disease.

Surgical technique versus functional outcome at last follow-up

Surgical technique did not influence functional outcome at last follow-up (pain: 41% symptoms

after AS versus 37% after OS, swelling: 29% versus 22%, stiffness: 13% versus 18%, limited range of

motion: 16% versus 21%, chronic analgesic treatment: 18% versus 12%).

Chronic analgesic treatment versus complications

24% (16/67) of patients using chronic analgesic treatment had a complication, compared with

10% (50/482) of patients without a complication.


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8

discussion

This international multicentre study offers new insights into the outcome of patients with the

orphan and heterogeneous disease diffuse-type Tenosynovial Giant Cell Tumour (TGCT). The

greatest strength of this dataset is that it represents the largest collection of surgically treated

diffuse-TGCT patients in the scientific literature, including RFS estimates for the knee, hip, foot/

ankle and upper extremity locations with long-term follow-up (>10 years). Oncologic results,

complications and functional results after surgical treatment are evaluated.

Oncologic outcome diffuse-TGCT

The fundamental question of whether curative treatment is necessary, or should be attempted in

non-lethal diffuse-TGCT often arises in literature. Debilitating symptoms and (progressive) joint

destruction commonly result from untreated diffuse-TGCT but can also occur following treatment.

At present, the choice of treatment is established by the preference of the patient, treating

physician and might differ by treatment centre. Surgical treatment for the locally aggressive diffuse-

TGCT is challenging, as pathologic tissue can be widely spread throughout the joint and may be

technically difficult to access and remove. In extensive disease, less than radical or only partial

resection could be preferred to improve symptoms with joint preservation in mind. However,

higher rates of recurrence have been described after macroscopically incomplete resections8, 29-31.

Some reports consider arthroscopic management of TGCT superior to open surgery, because of

less morbidity and a shorter recovery period32-36. Standard arthroscopy of the knee using only

anteromedial and anterolateral approaches however, does not allow surgical access to remove all

areas where diseased tissue is likely to be present. Therefore Blanco et al. and Mollon et al. used

multiple portals including posteromedial and posterolateral in arthroscopic synovectomy37-39. Chin

et al. stated that knee arthroscopy alone is an inferior treatment for extra-articular TGCT40. Open

synovectomy, either one- or two-staged, seems to be the preferred surgical approach to diffuse-

TGCT in most centres, because of tumour visibility and reported lower short-term recurrence

rates11, 41, 42. The disadvantage of a one- or two-staged open resection, could be deteriorated joint

function accompanied with decreased patient health-related quality of life13. A systematic review

showed lower recurrence rates for open synovectomy (average 14%, maximum 67%) compared

to arthroscopic synovectomy (average 40%, maximum 92%) in diffuse-TGCT11. Patel et al. (N=214)

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reported a statistically significant higher risk of recurrence in diffuse-type TGCT with arthroscopic

compared to open synovectomy (83.3% vs 44.8%, RR = 1.86 95% CI 1.32–2.62, P = 0.0004)9.

Palmerini et al. (N=206) did not find a difference in recurrence based on surgical technique for

localized- and diffuse-TGCT combined8.

A combined anterior arthroscopic- and posterior open synovectomy in the knee might be a

viable option, but is only incidentally reported. Mollon et al. described the combined approach

of a multiportal anterior and posterior arthroscopy and a posterior open synovectomy largely for

resection of extra-articular popliteal disease, and reported two recurrences in 15 patients38. Colman

et al. retrospectively evaluated 11 diffuse-TGCT patients treated by the combined approach and

also reported relatively low short-term recurrence rates (9%)43. A randomized controlled trial for

arthroscopic synovectomy versus open synovectomy has not been performed.

The present study calculated recurrence free survival rates for diffuse-TGTC at 3, 5 and 10 years

of 62%, 55% and 40%, respectively. This clearly underlines that with longer follow-up, recurrence

rates continue to increase (table 2-3, figure 3). The greatest risk factor for local recurrence is recurrent

disease at presentation in a tertiary centre (HR 3.5 95% CI 2.8-4.4 in multivariate analyses). In

therapy naïve patients with primary treatment in a tertiary centre, the largest risk factor for local

recurrence was arthroscopic synovectomy. The suspicion arises that more (macroscopic) tumour

tissue remains after arthroscopic synovectomy; however this largely depends on the extend of the

arthroscopy performed, whether multiple and posterior portals were used to access and remove

disease throughout the knee joint, and whether this approach is combined with an open approach

to remove residual intra-articular disease and/or extra-articular disease extension. However, none

of the assumed risk factors yielded significant differences when the analysis was performed in a

subgroup of therapy naïve patients with diffuse-TGCT affecting the knee. This could be attributed

to the near impossibility of achieving a complete macroscopic resection in widely spread, ill-

defined diffuse-TGCT patients and the impossibility of an R0 resection: macroscopically and

microscopically complete resection, neither with an arthroscopic- nor open resection.


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Multimodality treatment

Within the current era of systemic targeted and multimodality therapies (some only available

in trial settings) in TGCT, standalone surgical resection can no longer be regarded as the only

treatment for more severe diffuse forms of the disease. Surgery has been considered the treatment

of choice for decades, and the current study which included patients from 1990 onwards, consists

mainly of patients treated with a surgical procedure.

High recurrence rates, as confirmed by the present study, indicate the need for adjuvant therapies

to improve treatment outcomes for patients with diffuse-TGCT. Nonetheless, Gortzak et al. reported

no significant differences in residual disease, complication rates and overall physical and mental

health scores between patients surgically treated for TGCT of the knee with (N=34) or without (N=22)

adjuvant 90Yttrium, after a mean follow-up of 7.3 years17. Verspoor et al. evaluated 12 patients treated

with surgical synovectomy and additional cryosurgery. They did not find better results compared

to surgical resection alone44. Griffin et al. reported on 49 patients with diffuse-TGCT, most of whom

had both intra- and extra-articular and recurrent disease. They reported 3 (6%) recurrences following

synovectomy and radiation10. A meta-analysis suggested that open synovectomy (N=19 studies,

N=448) or synovectomy combined with perioperative radiotherapy (11 studies, N=123) is associated

with a reduced rate of recurrence16. Mollon et al. reserved the use of external beam radiation for

patients at high risk for local recurrence, if they had the following characteristics: multiple episodes

of recurrent intra-articular disease, extra-articular extension, or gross residual disease remaining

following surgery38. Currently, sufficient data including adequate patient numbers is lacking to

support the use of external beam radiation in primary cases, however the authors feel it should only

be performed in specific instances such as extensive or recurrent diffuse-TGCT cases.

In patients with locally advanced TGCT or (multiple) recurrence(s), systemic therapies targeting

the CSF1/CSF1R axis have been recently investigated including nilotinib, imatinib, pexidartinib

(PLX3397), emactuzumab (RG7155) and cabiralizumab (FPA008). Some systemic treatments for

TGCT have been proven to be effective18, 19, and novel and potentially more potent agents are

under investigation20-22. The disadvantages of adjuvant or targeted therapies are acute and long-

term side-effects of different degrees. Therefore, additional long-term follow-up studies in this

field remain indicated.

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Patients with aggressive disease accompanied with a high risk of recurrence following surgery

alone should be selected for (new) systemic and (neo)adjuvant treatment modalities. Diffuse-

TGCT presents as a heterogeneous disease with different disease severities. Some patients present

with tumours that are surgically relatively easy to access and these patients might not require

(neo)adjuvant therapies. Mastboom et al. defined the most severe diffuse-TGCT subgroup on MR

imaging as having diffuse-type TGCT including intra- and extra-articular disease and involvement

of at least one of the following three tissues: muscle, tendon or ligament)5. These patients seem

most eligible for multimodality or (neo)adjuvant strategies.

Complications

The literature on TGCT frequently lacks descriptions of complications after surgical treatment.

This study reported a complication rate of 12% following surgical management of patients with

diffuse-TGCT, predominantly after open resection (82%). The most common complication was joint

stiffness after open synovectomy, which might be difficult to prevent after the surgical treatment

of extensive disease. The true complication rate might be even higher, since it is suspected that

not all complications are scored.

Symptoms

TGCT related symptoms are mainly pain, swelling, stiffness and limited range of motion, but these

are reported with a great variability in degree and severity. Gelhorn et al. concluded that not

all patients experience all symptoms to the same extent (e.g. swelling but no pain, or pain and

swelling but no stiffness or limited range of motion)6. Symptoms prior to initial treatment at a

tertiary centre were compared for each patient with symptoms at last follow-up. Initial symptoms

of pain and swelling improved following treatment(s) in 43-56% of patients. This is comparable

with a crowdsourcing study in 337 TGCT patients originating from 31 countries14. In the majority

of patients, stiffness and limited range of motion did not seem to be principal symptoms either

initially, or at last follow-up. These symptoms are subjective for each patient and not all patients

were included with complete data. Nevertheless, pain and swelling are the main TGCT-related

complaints initially and frequently improve after surgical treatment(s).


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8

As expected, diffuse-TGCT patients with recurrent disease demonstrated higher rates of symptoms

at final follow-up, including a 3.5-fold higher rate of chronic analgesic use, compared to patients

without local recurrence at last follow-up. Also, patients using chronic analgesics had a higher rate

of complications.

Interestingly, after arthroscopic synovectomy in diffuse-TGCT, patients exhibited more pain,

swelling and a higher use of chronic analgesics, compared with open synovectomy. On the

contrary, open synovectomy was associated with higher rates of stiffness and limited range of

motion, which can be attributed to the larger surgical procedure resulting in additional scar tissue.

Joint specific analyses

Within this individual participant data meta-analysis, a homogeneous subgroup analysis for

diffuse-TGCT affecting the knee of therapy naïve patients was performed (figure 3b). Despite the

large number of patients in this study with diffuse-TGCT cases, the numbers in other joint locations

were too small to allow analysis of those specific groups.

Limitations

The main limitation of this study is selection (referral) bias, since data on patients treated at non-

specialized centres was lacking. Selection bias of affected joints seems absent when comparing

percentages of affected joints (table 1, figure 2) with a recent incidence calculation study including

nationwide coverage (in both studies 64% of diffuse-TGCT affects the knee)4.

Even though TGCT is a benign disease, particularly diffuse-TGCT can become a chronic illness

with substantial morbidity to the joint leading to functional and patient health-related quality

of life impairment, caused by the course of the disease itself and multiple treatments13. As data

were collected by local investigators or physicians according to the multicentre study design, data

quality depended on data registry on site. Only data available in the source data file of the patients

could be retrieved. In addition, interpretation of individual parameters could differ. No central

histopathological review was performed, as it was assumed that each centre provided the correct

diagnosis as set by their histopathology department. Within our study we did not collect which

patient had multiportal arthroscopy or standard anterior portal arthroscopy.

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Recurrence rates could either be over-estimated or under-estimated. Over-estimation could occur

because the follow-up status ‘alive with disease’ was classified as recurrence (if recurrence data

were missing). On the contrary, under-estimation could be present if patients with recurrent

disease, did not return at all or did not return to their original centre. It should be noted that

patients with recurrent disease had a longer follow-up compared to patients without recurrent

disease. The explanation could be that patients without symptoms and (assumed) without

recurrent disease were dismissed from follow-up and therefore had shorter follow-up times. In

addition, if treatments were recently performed, patients also had shorter follow-up times and are

still at risk of recurrence.

conclusion

This is the largest global individual data study on patients with diffuse-type TGCT and provides a

comprehensive and up to date disease overview, evaluating the clinical profile and management

of TGCT. Our study demonstrated that surgery is by far the most frequently performed treatment in

tertiary referral hospitals. However, even in specialised centres, local control of this heterogeneous

orphan disease, remains a major issue, with overall recurrence free survival of 55% at 5 years.

Since complete resection of diffuse-TGCT is often impossible and recurrence rates are high after

both arthroscopy and open synovectomy of the knee, the optimal surgical approach should be

left to the discretion of an experienced surgical and multidisciplinary team. However, in the era

of multimodality therapy, standalone surgical resection can no longer be regarded as the only

effective treatment for patients with diffuse-TGCT and alternative or combined approaches should

be considered.


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5. Mastboom MJL, Verspoor FGM, Hanff DF, Gademan MGJ, Dijkstra PDS, Schreuder HWB, Bloem JL, van der Wal RJP, van

de Sande MAJ. Severity classification of Tenosynovial Giant Cell Tumours on MR imaging. Surg Oncol. 2018;27:544-50.



7. Bhimani MA, Wenz JF, Frassica FJ. Pigmented villonodular synovitis: keys to early diagnosis. Clin Orthop Relat Res.

2001(386):197-202.







2012;118(19):4901-9.



2013;107(4):433-45.





2014;96-B(8):1111-8.


on Daily Living: Crowdsourcing Study on Physical Function and Quality of Life. Interactive journal of medical research.

2018;7(1):e4.

15. Heyd R, Seegenschmiedt MH, Micke O. [The role of external beam radiation therapy in the adjuvant treatment of

pigmented villonodular synovitis]. Zeitschrift fur Orthopadie und Unfallchirurgie. 2011;149(6):677-82.



J. 2015;97-B(4):550-7.



J. 2018;100-B(7):984-8.

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24. Honaker J, King G, Blackwell M. Amelia II: a program for missing data. J Stat Softw. 2011;45:1-54.

25. Rubin DB. Multiple imputation after 18+ years. J Am Stat Assoc. 1996;91:473-89.

26. Fay MP, Shaw PA. Exact and Asymptotic Weighted Logrank Tests for Interval Censored Data: The interval R package.

Journal of statistical software. 2010;36(2).

27. Sun J. A non-parametric test for interval-censored failure time data with application to AIDS studies. Statistics in

medicine. 1996;15(13):1387-95.

28. Anderson-Bergman C. icenReg: Regression Models for Interval Censored Data in R. J Stat Softw. 2017;81(12):1-23.




synovectomy, partial, arthroscopic synovectomy, and arthroscopic local excision. J Bone Joint Surg Am. 1992;74(1):119-

23.





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37. Blanco CE, Leon HO, Guthrie TB. Combined partial arthroscopic synovectomy and radiation therapy for diffuse pigmented

villonodular synovitis of the knee. Arthroscopy. 2001;17(5):527-31.

38. Mollon B, Griffin AM, Ferguson PC, Wunder JS, Theodoropoulos J. Combined arthroscopic and open synovectomy for

diffuse pigmented villonodular synovitis of the knee. Knee Surg Sports Traumatol Arthrosc. 2016;24(1):260-6.

39. Chang JS, Higgins JP, Kosy JD, Theodoropoulos J. Systematic Arthroscopic Treatment of Diffuse Pigmented Villonodular

Synovitis in the Knee. Arthroscopy techniques. 2017;6(5):e1547-e51.

40. Chin KR, Brick GW. Extraarticular pigmented villonodular synovitis: a cause for failed knee arthroscopy. Clin Orthop Relat

Res. 2002(404):330-8.

41. Flandry FC, Hughston JC, Jacobson KE, Barrack RL, McCann SB, Kurtz DM. Surgical treatment of diffuse pigmented

villonodular synovitis of the knee. Clin Orthop Relat Res. 1994(300):183-92.

42. Sharma V, Cheng EY. Outcomes after excision of pigmented villonodular synovitis of the knee. Clin Orthop Relat Res.

2009;467(11):2852-8.

43. Colman MW, Ye J, Weiss KR, Goodman MA, McGough RL, 3rd. Does combined open and arthroscopic synovectomy for

diffuse PVNS of the knee improve recurrence rates? Clin Orthop Relat Res. 2013;471(3):883-90.


Giant Cell Tumors. Sarcoma. 2016;2016:3072135.

trea

tmen

tlong-term efficacy of

imatinib mesylate in patients

with advanced tenosynovial giant

cell tumour

chap

ter

nine

M.J.L. Mastboom*1, F.G.M. Verspoor*2, G. Hannink2, R.G. Maki3, A. Wagner4, E. Bompas5, J. Desai 6, A. Italiano7, B.M. Seddon8, W.T.A.

van der Graaf9, J.-Y. Blay10, M. Brahmi10, L. Eberst10, S. Stacchiotti11, O. Mir12, M.A.J. van de Sande1, H. Gelderblom13, P. A. Cassier10

Submitted.

international, multicentre study

194

Chapter nine



3 Medical Oncology, Monter Cancer Centre & Cold Spring Harbor Laboratory, Long Island, NY, USA

4 Medical Oncology, Dana Farber Cancer Institute, Boston, USA

5 Medical Oncology, Institut de Cancérologie de l’Ouest, Nantes, France

6 Medical Oncology, Peter Mac Callum Cancer Centre, Melbourne, Australia

7 Medical Oncology, Institut Bergonié, Bordeaux, France

8 Medical Oncology, University College Hospital, London, United Kingdom

9 Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands

10 Medical Oncology, Centre Léon Bérard, Lyon, France

11 Medical Oncology, Istituto Nazionale Tumori, Milano, Italy

12 Medical Oncology, Gustave Roussy Institute, Villejuif, France



Imatinib in tenosynovial giant cell tumours

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9

abstract

Background

Tenosynovial Giant Cell Tumours (TGCT), are rare colony stimulating factor-1(CSF-1)-driven

proliferative disorders affecting joints. Diffuse-type TGCT often causes significant morbidity due

to local recurrences necessitating multiple surgeries. Imatinib mesylate (IM) blocks CSF-1 receptor.

This study investigated the long term effects of IM in TGCT.

Methods

We conducted an international multi-institutional retrospective study to assess the activity of

IM: data was collected anonymously from individual patients with locally advanced, recurrent or

metastatic TGCT.

Results

Sixty-two patients from 12 institutions across Europe, Australia and the United States were

identified. Thirty-nine patients were female (63%), median age at treatment start was 45 (range

20-80) years, with a median time from diagnose to treatment of 3.5 (range 0-38,2) years. Median

follow-up after treatment start was 52 (IQR 18-83) months. Four patients with metastatic TGCT

progressed rapidly on IM and were excluded for further analyses. Seventeen of 58 evaluable

patients achieved CR or PR. One- and five-year progression-free survival rates were 71% and 48%,

respectively. Thirty-eight (66%) patients discontinued IM after a median of 7 (range 1-80) months.

Reported adverse events in 45 (78%) patients were among other edema (48%) and fatigue (50%),

mostly grade 1-2 (89%). Five patients experienced grade 3-4 toxicities.

Conclusion

This study confirms, with additional follow-up, the efficacy of IM in TGCT. In responding cases we

confirmed prolonged IM activity on TGCT symptoms even after discontinuation, but with high

rates of treatment interruption and additional treatments.

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Chapter nine

introduction

Tenosynovial giant-cell tumour (TGCT), historically known as pigmented villonodular synovitis

(PVNS), is a rare, at times locally aggressive neoplasm affecting the joints or tendon sheaths in

young adults. It is most common around large joints such as the knees, ankles and hips1, 2. Known

subtypes are localized and diffuse TGCT. The localized subtype comprises a single nodule and has

a favourable course while the diffuse subtype involves the synovial lining as well as surrounding

structures and is associated with a significant risk of recurrence (>50% depending on follow up

times), despite being a benign neoplasm2-4. Metastatic forms have been described, but seem to

occur very rarely5, 6.

Surgical resection is the primary treatment for both subtypes. However, diffuse TGCT is difficult to

remove completely and often requires a total synovectomy, or at time a joint replacement, or rarely

even amputation1, 2, 7. In patients with extensive and/or recurrent TGCT, other available treatment

modalities include radiation synovectomy8, external beam radiation therapy9, and cryosurgery10.

Their therapeutic value has only been assessed in retrospective, in most cases single centre series

and their long term side effects and complications are poorly described11.

Recurrent TGCT is rarely lethal, but frequently becomes a debilitating chronic illness with

substantial morbidity to the joints and quality of life impairment, caused by the disease itself and

the multiple treatments2, 12.

In TGCT, a neoplastic clone constitutes a subpopulation (2-16%)13 of cells that overexpress colony-

stimulating factor-1 (CSF-1). A t(1;2) translocation that links the CSF1 gene on chromosome 1p13

to the COL6A3 gene on chromosome 2q35 has been described and is believed to be responsible

for the overproduction of CSF1 by neoplastic cells13, 14. Inhibition of CSF1/CSF-1 receptor (CSF-1R)

signaling has shown efficacy in the treatment of locally advanced and recurrent diffuse TGCT15-17.

Imatinib mesylate (IM) inhibits the CSF-1R kinase among other kinases17. We have previously

reported on the efficacy of IM in TGCT. In the present study we provide long term follow-up on

these initial patients and data on 33 additional consecutive patients.


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methods

This retrospective study was conducted at 12 referral centres across Europe (9 institutions), the

United States of America (2 institutions), and Australia (1 institution). The file of all patients with

locally advanced, recurrent or metastatic TGCT, treated with IM were reviewed. Patients information

were extracted from individual patients’ files at each institution by the local investigators and was

provided in an anonymous form for final analyses. Histopathologic examination was performed

at centre of origin by pathologists with extensive experience in mesenchymal tumours. Response

was measured using version 1.0 of Response Evaluation Criteria in Solid Tumours (RECIST). Data

were described using percentages for qualitative variables and medians with ranges for continuous

variables. Patients were not treated on a research protocol. They provided informed consent to

treatment with a ‘off-label’ medical treatment, and treatment decision was left to the treating

physician. This retrospective analysis was approved by the Ethics Committee in Lyon (Committee

for the Protection of Individuals, Sud-Est IV, Lyon, France – L10-153 dated 9 December 2010).

Survival was plotted using the Kaplan-Meier method. Progression-free survival (PFS) was

calculated from the date IM was started to the date of disease progression or death. The time to

treatment failure (TTF) was calculated from the date IM was started to the date it was stopped

because of toxicity, disease progression, or death, whichever occurred first. For patients with a

surgical resection or other additional therapy after treatment with IM, PFS and TTF were censored

at the time of surgery. Disease specific survival was calculated from the date IM was started to the

date of death due to TGCT. Symptomatic response was defined as improvement of pain and/or

joint function in patients who had symptoms at baseline. All statistical analyses were performed

using R version 3.4.0 (R Foundation, Vienna, Austria).

results

Patients

A total of 62 patients with histopathologically proven TGCT treated with imatinib were identified,

their main characteristics are described in Table 1. Briefly, median age at diagnosis was 39 (IQR

31-53) years and 45 (IQR 36-56) years at start of treatment with IM, the majority of patients were

female (N=39, 63%), and the knee (N=35, 56%) was the most commonly affected joint (Table 1). At

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Chapter nine

start of IM treatment, three (5%) patients had biopsy proven metastatic disease, 15 (24%) locally

advanced disease and 44 (71%) locally recurrent disease. Among patients with prior operations

for TGCT (n=47), the median number of prior operations was 2 (range 1-9), and the time since the

last operation was 23 (range 1-192) months. Median follow up of all patients was 52 (IQR 18-83)

months.

Treatment efficacy

Sixty-one patients received 400 mg and one patient received 600 mg IM daily. The 3 patients with

metastatic disease at treatment start progressed rapidly on IM and were excluded from further

analysis. One other patient with metastatic disease after multiple surgical treatments and IM, was

excluded for further analyses too, leaving 58 patients for the rest of the analysis.

Median duration of IM treatment was 9 (IQR 5-27) months. At last follow-up, the majority of patients

(n=38; 66%) had discontinued treatment. Seventy-seven percent (95% CI 67-89), 41% (95% CI 29-

57) and 36% (95% CI 25-52) of patients were still on IM after 6-, 12- and 24-months, respectively

(figure 1). The treatment failure-rate was 82% (95% CI 71-95) after 12 months.

Response could not be assessed in 3 patients, two of which were lost to follow-up and one who

discontinued early due to febrile neutropenia, leaving 55 patients with locally advanced or locally

recurrent TGCT assessable for response. Seventeen patients (31%; 95% CI 19-43) had a RECIST-

defined response, including 2 (4%) patients with a complete response. The median time to best

response was 6 (range 1-23) months.

Forty of 51 patients (78%) reported symptom improvement (table 2), including 14 of 15 patients

with radiological response (CR or PR). Among patients with radiological SD, 22 of 30 patients (73%),

for whom data was available, had symptom improvement.

The 1-, 2- and 5-years overall PFS, metastatic patients (N=4) excluded, was 71% (95% CI 60-85), 60%

(95% CI 48-75) and 48% (95% CI 36-65) respectively, (figure 2).


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Figu

re 1

Dur

atio

n of

imat

inib

mes

ylat

e tr

eatm

ent a

nd p

rogr

essi

on fr

ee s

urvi

val o

f thi

s tr

eatm

ent i

n pa

tient

s w

ith

loca

lly a

dvan

ced

or re

curr

ent d

iffus

e-ty

pe T

GC

T.

200

Chapter nine

Figure 2 Response and

follow

up of

imatinib

mesylate

in patients

with locally advanced or

recurrent diffuse-type

TGC

T. NED

= No evidence

of disease,

AWD

= A

live

with disease.


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9

Table 1 Descriptive of diffuse-type TGCT patients receiving imatinib mesylate treatment

Patients N (%)

Total 62 (100)

Median age at diagnosis (IQR), yrs 39 (31-53)

Median time from diagnosis to start IM (IQR), yrs 3.5 (1-8)

Sex

Male 23 (37)

Female 39 (63)

Tumour location

Knee 35 (56)

Ankle 11 (18)

Hip 6 (10)

Foot 4 (6)

Shoulder 1 (2)

Elbow 1 (2)

Head and Neck 2 (3)

Wrist 2 (3)

Surgery before start IM

None 15 (24)

1-2 24 (39)

3-4 13 (21)

>4 10 (16)

Median N of surgeries (range) 2 (1-9)

Median time since last surgery (range), mo 23 (1-192)

Disease status

Locally advanced 20 (32)

Recurrence after surgery 39 (63)*

Metastatic disease 3 (5)

Abbreviations: TGCT= Tenosynovial Giant Cell tumour, IM= imatinib mesylate, N= Number of patients,

mo=months, yrs= years. *One of the locally recurrent patients progressed to metastatic disease.

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Follow-up

Overall 38/58 patients (66%), metastatic patients (N=4) excluded, eventually discontinued IM after

a median of 7.0 (range 1-80 months). the most common reason for treatment discontinuation

was patient decision to stop (n=14, which possibly reflect low grade chronic toxicity), followed

by planned surgery (n=10), toxicity (n=7), physician’s decision (n=5) and progression (n=1). One

patient discontinued IM because of the diagnosis of another tumour requiring therapy. Among

the 27 patients who discontinued treatment for reasons other than surgery or progression,

progression (either radiological progression or requirement for another line of therapy – i.e.

surgery, other medical therapy or radiotherapy) eventually occurred 17 patients after a median of

12 (range 4-84) months, while 10 patients never progressed (nor required additional therapy) after

a median follow-up to 78 (range 1-109) months, suggesting that IM was able to provide prolonged

symptomatic relief at least in a proportion of patients.

Table 2 Summary of imatinib mesylate efficacy in patients with locally advanced or recurrent

diffuse-type TGCT

Parameter Patients N (%)

RECIST best response*

Complete remission 2 (4)

Partial response 15 (27)

Stable disease 36 (65)

Progressive disease 2 (4)

Overall response rate 17 (31)

Rate of disease control 53 (96)

Symptomatic response 40 (78)**

Median IM treatment duration (IQR), mo 9.3 (5-26)

Median PFS (IQR), mo 18 (8-55)

Abbreviations: TGCT= Tenosynovial Giant Cell tumour, IM= imatinib mesylate, N= Number of patients,

mo=months, yrs= years, IQR= inter quartile range. Overall response rate includes complete remission and

partial response; Rate of disease control includes complete remission, partial response and stable disease;

Symptomatic response was indicated as present or not (40/51=78%). Metastatic patients (n=4) were excluded.

*N=3 RECIST best response not available; **N=9 symptomatic response not available.


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9

Safety

Forty-five of 58 patients (78%), metastatic patients (N=4) excluded, reported at least one adverse

event with IM. The most common adverse events were edema (N=28, 48%), fatigue (N=29, 50%),

nausea (N=21, 34%) and skin rash/dermatitis (N=7, 12%), mostly grade 1-2 (89%). Additional grade

1-2 complaints were diarrhea, reflux, auditory hallucinations, conjunctivitis, sexual impairment,

asthenia, alopecia, cramps and dyspnea. Five (11%) patients had grade 3-4 toxicities, including

neutropenia, acute hepatitis, facial edema, skin toxicity and fatigue (table 3).

Table 3 Main toxicities associated with imatinib mesylate and reasons for discontinuation,

metastatic patients excluded

Patients N (%)

Variable All grades Grade 3-4

Edema/ fluid retention 28 (48) 1 (2)

Fatigue 29 (50) 1 (2)

Nausea 20 (34)

Skin rash/ dermatitis 7 (12) 2 (3)

Other* 15 (26) 3 (5)

Treatment status

Continued on IM 20 (34)

Stopped IM 38 (66)

Reason for stopping

Progression 1 (2)

Toxicity 7 (12)

Surgery 10 (17)

Patient choice 14 (24)

Physician decision 5 (9)

Other tumour 1 (2)

IM= imatinib mesylate, N= Number of patients. Forty-five (78%) patients reported at least one adverse event

with IM. *Other grade 1-2 complaints were diarrhea, reflux, auditory hallucinations, conjunctivitis, sexual

impairment, asthenia, alopecia, cramps and dyspnea. Five (11%) patients had grade 3-4 toxicities, including

neutropenia, acute hepatitis, auditory hallucinations.

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discussion

To our knowledge, this retrospective study provides the largest case series, with long follow-

up, of patients with locally advanced, recurrent or metastatic diffuse-type TGCT treated with IM.

We confirmed that IM has activity in TGCT with an overall response rate of 31% in patients with

locally advanced/recurrent TGCT. Interestingly all patients with metastatic TGCT progressed on IM,

suggesting that metastatic TGCT is either a different disease or loses its dependency on the CSF1/

CSF1R axis during malignant transformation. The main issue, is the drop-off rate, with more than

half of the patients discontinuing therapy within a year of therapy (59%; 95% CI 29-57), in most

cases for unclear reasons (patients decision, physician’s decision) suggesting an unfavourable

efficacy/toxicity balance. Eleven percent of patients reported grade 3-4 toxicities, which is

consistent with the rates reported with IM for adjuvant gastrointestinal stromal tumours (GIST) or

chronic myeloid leukaemia (CML)18-21.

To date, surgical resection remains the treatment of choice for diffuse-type TGCT, but is associated

with high recurrence rates and multiple additional surgeries11. It is challenging to balance between

increased morbidity of multiples or invasive surgeries12, 22, alternative therapeutic options, and daily

symptoms of the tumour. A more aggressive resection or other multimodality treatments, such as

external beam radiation therapy, radiosynovectomy and cryosurgery, may adversely affect joint

function, quality of life and development of osteoarthrosis, which, given the young age group, are

relevant factors2, 23. This would justify a less invasive approach, using systemic therapy, provided

those are associated with tumour shrinkage and, most importantly, symptomatic improvements24.

In the present study, age, localization and gender distribution were consistent with the literature10,

23, 25. The extent of disease in our patient group is emphasized by an disease specific survival of 90%

including four metastatic patients and 49% of patients had three or more surgeries before start

IM. Similar to previous case-series, we calculated a 1- and 5-years PFS of 71% and 48%, metastatic

patients excluded, respectively10, 23, 25. Because of heterogeneity of patients and a variety of

treatments, it is debatable to compare these numbers.

The overall response rate appears higher compared to nilotinib (6% (95% CI unknown), a different

tyrosine kinase inhibitor, with similar potency against CSF1R26. Our overall response rate (31%

(95% CI 19-43, metastatic patients (N=4) excluded) was consistent with our previous report on the


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9

short term results of IM (19% (95% CI 4-34) with similar disease control rate (96% versus 93%)17.

In the present study, 38 (66%) patients discontinued IM; 14 (37%) without subsequent treatment,

of which ten patients had stable disease at final follow up. Thirteen (62%) patients eventually

progressed, after discontinuing IM for toxicity or non-specific medical reason (N=21, 55%). Both

stable and progressive patients can be a result of discontinuing IM treatment or the natural course

of disease.

Newer, more specific inhibitors of CSF1R, currently only available in trial-setting such as

emactuzumab (RG7155)27, pexidartinib (PLX3397)15, and cabiralizumab28 (FPA008, Five-Prime),

have shown promising clinical activity on similar groups of diffuse TGCT patients in prospective

clinical studies with more formal criteria and timelines for response assessment than this

retrospective series. Emactuzumab (N=29)16 had an overall response rate of 86% (two patients


and symptomatic improvement (median follow up 12 months). Pexidartinib showed (N=23)15 an

overall response rate of 52% (all patients had a partial response) and a rate of disease control of

83%. Responses were associated with an improved joint function (median duration of response

exceeded eight months). The preliminary results with cabiralizumab (N=22) are consistent, with

radiographic response and improvement in pain and function in five out of 11 patients28. However,

long term efficacy data have not yet been reported with these newer agents.

Virtually all patients treated with IM for either CML or GISTs, experience29 at least one mild or

moderate adverse effect (grade 1-2). Toxicities of IM are determined by the disease stage and

the doses used, advanced disease and higher doses result in more frequent and severe toxicities.

Most side effects occur early in the course of treatment and tend to decrease in frequency and

intensity in time29. We consider a 10-15% rate of grade 3-4 toxicities in a generally benign but

locally aggressive disease, such as diffuse TGCT, too high. Only 22% of patients did not experience

any side effects.

Although target anti-cancer therapies are described as ‘well tolerated’, the perception of tolerability

may vary in the context of a, most often, benign condition. Understanding, monitoring and

managing the side effects will be important to optimize systemic therapy for patients with TGCT.

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Discontinuation of treatment due to toxicities was seen for IM (this series), emactuzumab15 and

pexidartinib16 in 12%, 20% and 9% patients, respectively. TGCT patients might be less willing to

cope with adverse event-related and study-related procedures. Here, we report prolonged clinical

benefit and symptomatic relief, even after discontinuation of treatment. A similarly persistent

effect was observed was also observed with monoclonal antibodies and more specific CSF1R

tyrosine kinase inhibitors this24. This suggest that intermittent treatment administration may be

an option to improve long term tolerability.

The place of systemic treatment in a benign, locally aggressive disease, such as TGCT, and how to

optimally deliver this treatment, remains unclear. More specifically, the role of CSF1R inhibitors

in the peri-operative setting still needs to be explored: the number of patients who underwent

operation after IM in our series is too low to draw any conclusions. Despite limitations related to

its retrospective nature, this study adds to the knowledge of targeting the CSF-1/CSF-1R pathway

in patients with TGCT. An optimal treatment strategy should be developed for the patient group

that benefits most from systemic therapy. The combination of a short period of treatment and the

durable effect after discontinuation, should be pursued. It is challenging to maintain compliance

for years, especially with, even “minor”, toxicities, in the context of a non-life-threatening disease.

A limitation of all, including this, clinical TGCT studies is the lack of a control group and the

absence of specific and validated patient-reported outcome measures to document treatment-

induced symptomatic, functional and economic (back to work) improvement16. Quality of life and

functional forms should be implemented. These measures are critical endpoints in demonstrating

clinical relevance and impact of treatments for benign diseases in which death is not a relevant

outcome variable30. Clinical benefit necessitates objective measures to correlate with tumour

reduction.


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9

conclusion

Identification of a biologic aggressive subgroup of diffuse TGCT, at risk of increased surgical

morbidity or recurrent disease, should aid to decide which patients benefit most of systemic

treatments. With the advent of more potent CSF-1R inhibitors, such as emactuzumab, pexidartinib

and cabiralizumab, the role of IM in extensive TGCT might weaken, but may be balanced by the

favourable safety profile of IM. Availability of these new compounds, both in terms of registration

and reimbursement, will ultimately define the prescribed drug in daily practice.

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15. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, et al. Structure-Guided Blockade of CSF1R

Kinase in Tenosynovial Giant-Cell Tumor. The New England journal of medicine. 2015;373(5):428-37.

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28. Sankhala KK, Blay J-Y, Ganjoo KN, Italiano A, Hassan AB, Kim TM, et al. A phase I/II dose escalation and expansion

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Giant Cell Tumors. Clin Ther. 2016;38(4):778-93.

qual

ity

oF l

iFe

the effect of surgery in


as measured by patient reported

outcomes on quality of life and

joint function

chap

ter

ten

M.J.L. Mastboom*1, F.G.M. Verspoor*2, G. Hannink2, W.T.A. van der Graaf3 , M.A.J. van de Sande1, H.W.B Schreuder2

Accepted in Bone Joint J.

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3 Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands


Quality of life and joint function in tenosynovial giant cell tumours

213

10

abstract

Aim

To evaluate health-related quality of life (HRQoL) and joint function in TGCT patients before and

after surgical treatment.

Patients and methods

This prospective cohort study run in two Dutch referral centres, assessed patient-reported outcome

measures (SF-36, VAS and WOMAC) in 359 consecutive patients with localized- and diffuse-type

TGCT of large joints. Patients with recurrent disease (N=121) and a wait-and-see policy (N=32)

were excluded. Collected data were analysed at specified time intervals pre-(baseline) and/or

postoperatively up to 5 years.

Results

In total 206, 108 localized- and 98 diffuse-type, TGCT patients were analysed. Median age at

diagnosis of localized- and diffuse-type was 41 (IQR 29-49) and 37 (IQR 27-47) years, respectively.

SF-36 analyses showed statistically significant and clinically relevant deteriorated preoperative-

and direct postoperative scores compared with general population means, depending on subscale

and TGCT subtype. After 6 months of follow up, these scores improved to general population

means and continued to be fairly stable the following years. VAS scores, for both-subtypes,

showed no clinically relevant differences pre- or postoperatively. Pain experience varied hugely

between patients and also over time. WOMAC scores, for both TGCT subtypes, showed no clinically

relevant differences pre- versus postoperatively. However, in diffuse-type patients WOMAC pain

and physical function scores showed a trend towards improvement postoperatively.

Conclusion

Patients report a significant better HRQoL after surgery in TGCT whereas joint function showed

a trend towards improvement. Pain scores –which vary hugely between patients and in patients

over time- did not improve. A disease specific patient-reported outcome measure would help to

decipher impact of TGCT on patients’ daily life and functioning in more detail.

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Chapter ten

introduction

Tenosynovial giant cell tumours (TGCT) of large joints, historically known as pigmented villonodular

synovitis (PVNS), are rare colony stimulating factor-1 (CSF-1)-driven proliferative, mono-articular

disorders. They affect the joints or tendon sheaths at all ages, however mostly at young adulthood. It

most commonly affects large, weight bearing joints such as knees, ankles and hips1, 2. The incidence

rate of localized-extremity (excluding digits) and diffuse-type TGCT is 10 and 4 per million person

years, respectively3. Localized-type comprises a single nodule and has a favourable course after

surgical treatment. Diffuse-type involves the synovial lining as well as surrounding structures. It

can behave locally aggressive and is challenging to remove completely. There is a significant risk of

recurrence after surgical treatment (>50% depending on follow up times)2, 4, 5.

Diffuse-type TGCT often requires one or multiple synovectomies, or at times a joint replacement,

and rarely even amputation1, 2, 6. In patients with extensive and/or recurrent TGCT, other available

treatment modalities include radiation synovectomy7, external beam radiation therapy8, and

cryosurgery9 of which the effects are controversial10. More recently, systemic therapy has been

introduced, targeting the CSF-1 receptor. At first treatment with the multi targeting tyrosine

kinase inhibitor imatinib started, very recently more promising data of a CSF-1 specific targeting

agent were presented11-13. Systemic treatment may need to be given for one to several years, but

the optimal treatment duration has still to be determined. Despite the variety of treatments, it is

unclear which one is the most effective with the least impact on quality of life.

A limitation of most clinical TGCT studies is the absence of disease specific and validated patient-

reported outcome measures (PROMs) to document disease and treatment related functioning and

symptomatology. Overall survival is the primary endpoint in oncologic clinical trials, however this

is not appropriate for TGCT, which is rarely lethal14. Alternate treatment endpoints in TGCT include

response rates, progression free survival, and avoidance of morbid therapies. As indicated, quality

of life (QoL) and functional scores are of utmost importance, but they are mostly not reported

or only described for small, heterogeneous patient groups2, 15. The impact of therapies and the

relevance of treatment outcomes to patients’ quality of life is therefore essential especially in a

benign but locally aggressive disease16,17.


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10

The aim of our study is to investigate HRQoL, pain and joint function in surgically treated non-

recurrent TGCT patients, pre- and/ or postoperatively over time.

methods

This prospective cohort study was conducted at two Dutch referral centres; Radboud University

Medical Centre (RadboudUMC) and Leiden University Medical Centre (LUMC). Between 2011 until

2018 patients diagnosed with primary therapy-naïve or recurrent TGCT (magnetic resonance

imaging (MRI) and histological confirmed) of large joints, were asked to participate. Large

joints were defined as all joints except the digits. Three hundred and fifty-nine consecutive

patients were identified; 136 (38%) with localized TGCT, 223 (62%) with diffuse TGCT. During

regular outpatient clinic visits, patients who consented were requested to complete PROMs

questionnaires. To further reduce heterogeneity of the group, patients with recurrent disease at

presentation, treated conservatively (wait-and-see policy) and patients in absence of QoL and

function scores after primary surgery, were excluded from this analysis (figure 1). Also, if patients

developed relapse after surgical treatment, they were excluded from this time on. Hundred-and-

eight localized- and 98 diffuse-type therapy-naïve patients were used for final analyses (figure 1).

The study protocol (RadboudUMC (file number CMO 2012/555) and LUMC (file number CMO

P13.029)) was approved by the local institutional ethical review boards and was carried out in

the Netherlands in accordance with the applicable rules concerning the review of research ethics

committees and informed consent. Patients provided written informed consent when they

completed questionnaires (SF 36, VAS and WOMAC).

The used PROMs included the Dutch translation of a generic HRQoL instrument, the 36-item

Short Form Health Survey (SF-36)18, a Visual Analog Scale (VAS) for pain and the Western Ontario

and McMaster Universities Osteoarthritis Index (WOMAC). SF-36 is an instrument for measuring

general health, including eight subscales: Physical functioning (PF), Social functioning (SF),

Role limitations due to physical problems (RP), Role limitations due to emotional problems (RE),

General mental health (MH), Vitality (VT), Bodily pain (BP) and General health (GH). SF-36 scores

were computed by summing the item scores and transforming the scores onto a 100-point scale

(0= “worst health” and 100= “best health”). VAS for worst pain was used to estimate patients pain

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Chapter ten

Figure 1 Flowchart of consecutive patients with TGCT, included for quality of life analyses.

*Additional cryosurgery in two localized- and five diffuse-type TGCT patients

evaluated TGCT patientsN=359

therapy naive patientslocalized, N=127diffuse, N=142

ExcludedRecurrent TGCT

localized, N=9diffuse, N=81

Localized-TGCTN=108

Diffuse-TGCTN=98

arthoscopic synovectomy, N=3

one-staged synovectomy, N=103*

prosthesis, N=2

arthoscopic synovectomy, N=3

one-staged synovectomy, N=75*

two-staged synovectomy, N=18*

prosthesis, N=2

ExcludedNo PROMS available prior to first recurrens


Excluded’Wait and see policy’



217

10

intensity of the affected joint for the past 24 hours, using a series of 0- to 10-point (0= “no pain”

and 10= ”pain as bad as you can imagine”)19. The Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC) was used to evaluate affected joint function20. The WOMAC is a

24-item instrument assessing pain, stiffness and difficulty performing daily activities originally

designed for osteoarthritis. All items are measured on a 5 point scale; ranging from “no” up to

“worst imaginable”. The WOMAC data were standardized to a range of values from 0-100, for which

lower values indicate more pain, more stiffness, or worse physical functioning. Gelhorn et al. 16

used a modified version of WOMAC for TGCT patients.

Patient demographics and clinical, histological, radiological, treatment and follow-up data were extracted

from individual patients’ files at each institution by the local investigator (FGMV or MJLM) and were

provided in an anonymous form for analyses. Definitive histological diagnosis was performed at the centre

of origin by dedicated pathologists with extensive experience in mesenchymal tumours. Recurrences

and PROMs were analysed according to TGCT subtype. Data were described using percentages for

qualitative variables and medians with interquartile ranges (IQR) for continuous variables.

As patient questionnaires were completed at different points in time they were categorized in the

following time intervals: pre-surgery (=0 or baseline), post-surgery after 0-3, 3-6, 6-12, 12-24, 24-36,

36-48, 48-60 months. At final analyses we did not have questionnaires in all time intervals for each

individual patient, some had solely pre- or post-operative scores. In case of recurrent disease after

primary treatment in a therapy-naïve patient, QoL and functions scores were used up to recurrence

development, confirmed on MR imaging. Follow-up time was defined as the period between first TGCT

confirmation (MR imaging and histologic) and most recent patient contact. Time to recurrence was

calculated as time from first treatment until proven (MR imaging and histologic) first recurrent disease.

Differences between QoL scores (SF-36, VAS, WOMAC) were tested using t-tests. SF-36 scores were

compared with Dutch general population scores18, and WOMAC and VAS baseline (preoperative)

scores were compared with postoperative scores.

To estimate the clinical relevance, the mean differences were compared with the minimal clinically

important difference (MCID). MCID is a QoL measure that represents the smallest difference or

change beyond statistical significance in an outcome measure score that would be considered

clinically relevant by the value patients place on change21. The MCID for SF-36 has been estimated

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Chapter ten

at to be 10 points by Escobar et al.22 in patients undergoing total knee replacement. For VAS pain

a MCID of 2 was used23. The MCID for standardized WOMAC values has been estimated at around

15-20 points22, with relative improvements of 21-41% for its subscales23-25. We used a MCID for

WOMAC of 20 points based on consensus in the project team and the study of van der Wees et al.26

All statistical analyses were performed using R version 3.4.0 (R Foundation for Statistical Computing,

Vienna, Austria). P-values <0.05 were considered statistically significant.

results

Patients

After exclusion of patients with recurrent disease (N=121) and patients with a wait-and-see policy

(N=32), 206 patients remained for further analyses (figure 1). Median age at diagnosis of localized-

(N=108) and diffuse-type (N=98) TGCT was 41 (IQR 29-49) and 37(IQR 27-47) years, respectively. The

majority of patients were female (localized N=62 (57%)), had diffuse-type TGCT N=64 (65%)), and had

the knee as the most common affected joint in both subtypes (localized N=84 (78%)) and diffuse N=72

(74%)). Pain (localized N=61 (57%) and diffuse N=58 (60%)) and swelling (localized N=66 (61%) and

diffuse N=65 (67%)) were the most prevalent clinical symptoms at diagnosis for both subtypes (table 1).

Treatments

As primary treatment, three (3%) localized-type patients were treated with arthroscopic

synovectomy, 103 (95%) with one-staged synovectomy and two (2%) with (endo-)prosthesis. Seven

patients (6%) had a first recurrence after median 2.9 (2.1-5.6) years. Overall median follow up of

localized therapy-naïve patients was 2.0 (IQR 0.7-4.6) years. At final follow up, 104 (96%) patients

had no evidence of disease, 4 (4%) patients were alive with disease, without planned treatment.

Diffuse-type patients were treated with arthroscopic (N=3 (3%)), one-staged (N=75 (76%)) or two-

staged (N=18 (19%)) synovectomy. Two patients received an (endo-) prosthesis. Twenty-seven

patients (28%) had a first recurrence after median 1.3 (1-3) years, thereafter they were excluded

from further analyses. Overall median follow up of diffuse-type patients was 2.7 (IQR 1.4-4.9) years.

At final follow up, 70 (71%) patients had no evidence of disease, 27 (28%) patients were alive with

disease and one patient died of another disease.


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10

Table 1 Characteristics of therapy-naïve TGCT patients

Localized N (%) Diffuse N (%)

Total 108 98

Median age at diagnosis (IQR), yrs. 41 (29-49) 37 (28-47)

Sex

Male 46 (43) 34 (35)

Female 62 (57) 64 (65)

Tumour localization

Knee 84 (78) 72 (74)

Ankle 10 (9) 10 (10)

Hip 1 (1) 7 (7)

Other 13 (12) 9 (9)

Pre-surgery symptoms

Pain 61(57) 58 (60)

Swelling 66 (61) 65 (67)

Loss of function 8 (7) 20 (21)

Stiffness 5 (5) 14 (14)

Recurrent disease

No 101 (94) 71 (72)

Yes 7 (6) 27 (28)

Median time to first recurrence (IQR) 2.9 (2.1-5.6) 1.3 (1-3)

Complications

None 106 (98) 91 (93)

Deep wound infection - 2 (2)

Superficial wound infection 1 (1) 2 (2)

Hemorrhage - 1 (1)

Joint stiffness 1 (1) 1 (1)

Neurovascular damage - 1 (1)

Median follow up time (IQR), yrs 2.0 (0.7-4.6) 2.7 (1.4-4.9)

Abbreviations: TGCT= Tenosynovial Giant Cell Tumours, N= Number of patients, mo=months, yrs= years, IQR= inter quartile range, other= Foot, shoulder, elbow, wrist or temporomandibular joint, AWD= alive with disease.

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Chapter ten

HR Quality of life

Compared to Dutch general population means18, localized-type patients preoperatively scored

significantly lower on PF(13.2(95%CI 6.0-20.5)), SF(18.7(95%CI 10.3-27.2)), RP(25.8(95%CI 11.9-39.8)),

RE(20.6(95%CI 7.3-34.0)) and BP(21.2(95%CI 12.7-29.8)). These differences were also clinically relevant

(mean difference> MCID 10). This effect lasted up to 3 months postoperatively on RP(40.1(95%CI

16.7-63.5)) and BP(17.2(95%CI 2.2-32.1)). Thereafter, these means improved to general population

means and continued fairly stable during the following years (figure 2a, table 2b).

Figure 2a SF-36 scores of localized-type, therapy-naïve, TGCT patients.

Spider plot showing SF-36 scores preoperative (baseline), 6-12 months postoperatively and of Dutch general

population means18: physical functioning (PF), social functioning (SF), role limitations due to physical problems

(RP), role limitations due to emotional problems (RE), general mental health (MH), vitality (VT), bodily pain (BP)

and general health (GH).


221

10

Figure 2b SF-36 scores of diffuse-type, therapy-naïve, TGCT patients.

Spider plot showing SF-36 scores preoperative (baseline), 6-12 months postoperatively and of Dutch general

population means18: physical functioning (PF), social functioning (SF), role limitations due to physical problems

(RP), role limitations due to emotional problems (RE), general mental health (MH), vitality (VT), bodily pain (BP)

and general health (GH).

Diffuse-type patients preoperatively scored statistically significant and clinically relevant (mean

difference> MCID 10) lower on PF(23.7 (95% CI 16.7-30.8)), SF (15.6 (95% CI 8.8-22.5)), RP (37.4

(95% CI 25.3-49.5)), VT (10.0 (95% CI 3.5-16.4)) and BP (21.6 (95% CI 14.7-28.5)) compared to

general population means. This difference with the general population remained significant for

up to 3 months postoperatively on PF (21.9 (95% CI 5.0-38.8)), SF (19.9 (95% CI 3.0-36.9)), RP (40.1

(95% CI 16.2-64.1)), VT (13.0 (95% CI 1.5-24.5)) and BP (22.4 (95% CI 5.3-39.4)) and up to 6 months

222

Chapter ten

Table 2a SF-36 scores of localized-type, therapy-naïve, TGC

T patients preoperatively and postoperatively up to 5-years follow up com

pared

with general population m

eans.

SF-36 subscalesG

eneral p

opulation

(mean (SD

))

Time intervals in m

onths

0N

=420-3

N=14

3-6N

=116-12

N=15

12-24N

=1624-36N

=1536-48N

=1048-60N

=8

Physical functioning (PF)81.9 (23.2)

68.7* (23.0)67.1 (23.8)

69.1 (22.6)74.3 (16.7)

78.8 (19.9)77.0 (17.9)

73.0 (33.0)75.6 (23.7)

Social functioning(SF)

86.9 (20.5)68.2* (26.9)

81.3 (22.3)87.5 (17.7)

80.0 (22.1)85.9 (19.3)

83.3 (21.5)71.3 (27.7)

76.6 (29.5)

Role physical(RP)

79.4 (35.5)53.6* (44.7)

39.3* (43.5)56.8 (40.5)

66.7 (38.6)78.1 (36.4)

71.7 (32.6)72.5 (41.6)

71.9 (38.8)

Role emotional

(RE)84.1 (32.3)

63.5* (42.8)88.1 (28.1)

81.8 (40.5)86.7 (27.6)

77.1 (35.9)88.9 (24.1)

90.0 (31.6)83.3 (35.6)

Mental health

(MH

)76.8 (18.4)

70.1 (18.9)79.4 (17.5)

83.3 (14.3)85.6 (15.3)

74.8 (17.3)81.1 (11.3)

83.2 (11.9)80.5 (19.4)

Vitality(V

T)67.4 (19.9)

60.6 (20.9)66.2 (20.4)

67.3 (23.4)73.3 (18.4)

60.9 (14.2)69.0 (16.9)

61.5 (24.7)63.8 (25.0)

Bodily pain(BP)

79.5 (25.6)58.3* (27.3)

62.3* (27.8)71.1 (25.8)

69.5 (18.9)74.7 (25.3)

71.7 (24.1)72.8 (33.0)

71.3 (33.4)

General health

(GH

)72.7 (22.7)

66.4 (18.3)65.0 (14.1)

73.2 (15.2)67.7 (16.4)

64.4* (15.4)70.0 (17.7)

63.5 (22.1)65.0 (15.1)

N= num

ber of questionnaires. *=statistically significant, underlined scores are clinically relevant (mean difference > M

CID 10). SF-36 questionnaires w

ere

categorized in the following tim

e intervals: pre-surgery (0), post-surgery after 0-3, 3-6, 6-12, 12-24, 24-36, 36-48, 48-60 months.


223

10

Tabl

e 2b

SF-

36 s

core

s of

diff

use-

type

, the

rapy

-naï

ve, T

GC

T pa

tient

s pr

eope

rativ

ely

and

post

oper

ativ

ely

up to

5-y

ears

follo

w u

p co

mpa

red

with

gen

eral

pop

ulat

ion

mea

ns.

SF-3

6 su

bsca

les

Gen

eral

po

pula

tion

(mea

n (S

D))

Tim

e in

terv

als

in m

onth

s

0N

=47

0-3

N=1

43-

6N

=17

6-12

N=1

712

-24

N=1

724

-36

N=1

536

-48

N=1

548

-60

N=1

3

Phys

ical

func

tioni

ng (P

F)81

.9 (2

3.2)

58.2

* (2

3.7)

60.0

* (3

1.6)

67.1

* (2

3.6)

79.4

(12.

0)71

.8 (2

2.2)

72.3

(18.

9)73

.3 (2

5.0)

79.6

(17.

1)

Soci

al fu

nctio

ning

(SF)

86.9

(20.

5)71

.3*

(23.

2)67

.0*

(31.

6)75

.0 (2

5.8)

85.3

(14.

8)88

.2 (1

6.8)

85.8

(16.

3)82

.5 (2

7.9)

86.5

(15.

7)

Role

phy

sica

l(R

P)79

.4 (3

5.5)

42.0

* (4

0.7)

39.3

* (4

4.6)

60.3

(44.

2)85

.3 (2

8.0)

75.0

(36.

4)70

.0 (4

0.3)

78.3

(37.

6)90

.4 (1

6.3)

Role

em

otio

nal

(RE)

84.1

(32.

3)72

.3 (4

0.1)

78.6

(38.

4)86

.3 (2

9.0)

92.2

(18.

7)82

.4 (3

5.6)

93.3

(18.

7)84

.4 (3

5.3)

92.3

(20.

0)

Men

tal h

ealth

(MH

)76

.8 (1

8.4)

71.0

(18.

4)74

.3 (1

5.6)

78.4

(14.

0)78

.4 (1

6.3)

75.8

(20.

1)78

.4 (1

4.9)

74.9

(22.

0)77

.8 (1

8.6)

Vita

lity

(VT)

67.4

(19.

9)57

.4*

(21.

8)54

.4*

(21.

4)62

.4 (2

1.1)

71.2

(19.

9)61

.2 (2

3.0)

63.7

(18.

8)66

.3 (2

8.4)

65.4

(23.

5)

Bodi

ly p

ain

(BP)

79.5

(25.

6)57

.9*

(23.

1)57

.1*

(31.

7)70

.0 (2

2.3)

77.9

(17.

0)77

.2 (2

3.0)

70.0

* (1

6.9)

76.0

(22.

5)79

.4 (2

2.1)

Gen

eral

hea

lth

(GH

)72

.7 (2

2.7)

63.9

* (1

3.6)

63.6

(19.

1)62

.9*

(13.

6)62

.1*

(16.

9)62

.4*

(19.

9)62

.0*

(11.

6)65

.7 (1

7.3)

66.9

(15.

2)

N=

num

ber

of q

uest

ionn

aire

s. *=

stat

istic

ally

sig

nific

ant,

unde

rline

d sc

ores

are

clin

ical

ly r

elev

ant

(mea

n di

ffere

nce

> M

CID

10)

. SF-

36 q

uest

ionn

aire

s w

ere

cate

goriz

ed in

the

follo

win

g tim

e in

terv

als:

pre

-sur

gery

(0),

post

-sur

gery

aft

er 0

-3, 3

-6, 6

-12,

12-

24, 2

4-36

, 36-

48, 4

8-60

mon

ths.

224

Chapter ten

postoperatively on PF (14.8 (95% CI 3.3-26.4)). Thereafter, the mean SF-36 scores of diffuse-type

patients improved to Dutch general population means and continued fairly stable the following

years. Compared to general population means diffuse-type patients scored statistically significant

and clinically relevant lower on GH 3-6 months (10.6 (95% CI 9.8-23.2)), 6-12 months (10.3 (95% CI

2.3-18.9)) and 24-36 months (10.7 (95% CI 4.5-16.9)) postoperatively (figure 2b, table 2b).

Visual analog scale for pain

No statistical significant nor clinical relevant difference in pain scores were found in localized-type

patients preoperatively (median VAS score 4, IQR 1-6) versus 3 months postoperatively (median

VAS score 3.5, IQR 1-5), which in fact remained the same up to five years follow up. Median VAS

scores in diffuse-type patients showed no clinical relevant difference preoperatively (median VAS

score 4, IQR 2-6) versus 3 months postoperatively (median VAS score 2, IQR 1-4), and also here the

scores remained the same up to five years follow up. Pain experience in both subtypes TGCT varied

widely between and within patients over time (range 0-7 years follow up).

Joint function

Mean WOMAC scores on pain, stiffness and physical functioning for both localized- and diffuse-

type patients showed no significant differences pre-(baseline) versus postoperatively. Patients

of both subtypes scored significantly better at some postoperative time intervals compared to

baseline scores, however mostly clinically irrelevant (mean difference< 20) (table 3a and b).

In diffuse-type patients (table 3b) WOMAC pain and physical function scores showed a trend

towards improvement in scores from preoperatively (baseline) to postoperative up to 5 years

follow-up.


225

10

Tabl

e 3a

WO

MAC

sco

res

of lo

caliz

ed-t

ype,

ther

apy-

naïv

e, T

GC

T pa

tient

s pr

eope

rativ

ely

and

post

oper

ativ

ely

up to

5-y

ears

follo

w u

p

WO

MAC

sco

res

(mea

n (S

D))

Tim

e in

terv

als

in m

onth

s

0N

=35

0-3

N=1

23-

6N

=96-

12N

=14

12-2

4N

=924

-36

N=8

36-4

8N

=548

-60

N=5

Pain

73.1

(20.

9)74

.2 (1

7.4)

86.7

* (1

3.7)

83.9

(16.

5)70

.0 (2

2.4)

85.0

* (1

1.0)

81.0

(29.

2)95

.0*

(5.0

)

Stiff

ness

73.5

(25.

1)59

.4 (1

9.3)

77.8

(21.

4)79

.5 (2

5.8)

59.7

(32.

3)67

.2 (2

5.8)

85.0

(22.

4)80

.0 (1

1.2)

Phys

ical

75.0

(21.

4)76

.5 (1

9.4)

88.1

* (1

3.1)

89.8

* (1

1.8)

74.7

(20.

6)86

.0 (1

1.6)

82.1

(33.

9)92

.6*

(7.1

)

Tota

l74

.7 (2

0.1)

74.6

(17.

8)87

.4*

(13.

5)87

.7*

(13.

0)72

.5 (2

1.3)

84.2

(10.

6)82

.1 (3

1.8)

92.1

* (6

.6)

WO

MAC

= st

anda

rdiz

ed W

este

rn O

ntar

io a

nd M

cMas

ter

Uni

vers

ities

Ost

eoar

thrit

is In

dex.

In t

he s

tand

ardi

zed

WO

MAC

(0-

100)

sum

sco

res,

high

er v

alue

s

indi

cate

less

pai

n, s

tiffne

ss o

r be

tter

phy

sica

l fun

ctio

ning

. N=

num

ber

of q

uest

ionn

aire

s.*=s

tatis

tical

ly s

igni

fican

t, un

derli

ned

scor

es a

re c

linic

ally

rel

evan

t

(mea

n di

ffere

nce

> M

CID

20)

. WO

MAC

que

stio

nnai

res w

ere

cate

goriz

ed in

the

follo

win

g tim

e in

terv

als:

pre

-sur

gery

(0),

post

-sur

gery

aft

er 0

-3, 3

-6, 6

-12,

12-

24,

24-3

6, 3

6-48

, 48-

60 m

onth

s.

226

Chapter ten

Table 3b WO

MAC scores of diffuse-type, therapy-naïve, TG

CT patients preoperatively and postoperatively up to 5-years follow

up

WO

MAC scores

(mean (SD

))

Time intervals in m

onths

0N

=310-3

N=11

3-6N

=106-12N

=912-24N

=1224-36N

=1136-48N

=1048-60N

=9

Pain59.8 (20.9)

68.2 (23.5)73.5 (17.2)

75.6 (21.0)79.6* (22.7)

77.7* (20.8)77.5* (22.8)

85.0* (21.2)

Stiffness60.9 (24.1)

62.5 (17.7)76.3 (24.6)

69.4 (19.9)68.8 (22.3)

69.3 (18.8)72.5 (21.1)

75.0 (25.8)

Physical63.9 (18.8)

68.3 (18.7)73.7 (22.2)

82.7* (15.7)81.0* (23.1)

76.7 (21.5)82.1* (18.2)

84.2* (19.5)

Total62.8 (18.7)

67.8 (18.4)73.9 (20.3)

80.1* (16.1)79.7* (22.4)

76.3 (20.2)80.3* (18.0)

83.6* (19.4)

WO

MAC= standardized W

estern Ontario and M

cMaster U

niversities Osteoarthritis Index. In the standardized W

OM

AC (0-100) sum scores, higher values

indicate less pain, stiffness or better physical functioning. N= num

ber of questionnaires.*=statistically significant, underlined scores are clinically relevant

(mean difference > M

CID 20). W

OM

AC questionnaires were categorized in the follow

ing time intervals: pre-surgery (0), post-surgery after 0-3, 3-6, 6-12, 12-24,

24-36, 36-48, 48-60 months.


227

10

discussion

To our knowledge, this study provides the largest prospective cohort, including longest follow up

time, to report on PROMs in therapy-naïve patients with localized- and diffuse-type TGCT of large

joints followed up until relapse of disease or end of study. In both TGCT subtypes HRQoL (SF-36)

was statistically significant and clinically relevant decreased before surgical treatment on the main

physical domains (RP, PF, BP) and some mental domains (SF, RE, VT) compared to general population

means. These low scores lasted for up to 6 months postoperatively depending on TGCT subtype and

SF-36 subscale. Thereafter, all SF-36 subscales improved to general population means and continued

fairly stable the following years. Pain experience (VAS) in both subtypes varied widely between and

within patients over time. Mean function (WOMAC) scores on pain, stiffness and physical functioning

for both subtypes TGCT showed no clinically relevant difference pre-(baseline) versus postoperatively.

However, in diffuse-type patients WOMAC pain and physical function scores showed a trend towards

improvement in scores from preoperatively(baseline) to postoperatively up to five years follow-up.

TGCT can behave locally aggressive causing joint destruction and provoke significant pain, swelling,

decrease in range of motion, and stiffness11. This morbidity can lead to impairment of HRQoL and

function because of pain, medication use, disability, the knowledge of having a tumour (despite

its benign character), and loss of working hours16. To improve these consequences, treatments are

performed, which –unfortunately- might contribute to further joint destruction10. The prolonged

course of the disease and the need for multiple surgeries has been reported to result in a worse

joint function for many patients27. In addition to the physical and financial burden for the patient,

TGCT also involves high healthcare burden28. Finding an efficient treatment is important.

This study reported on the loss of HRQoL in patients with TGCT compared to general population

means. The improvements in HRQoL after surgical resections were present 3-6 months after surgery.

This could be explained by the morbidity of an operation and the associated recovery time.

We did not find statistically significant and clinically relevant differences in pain experience. This

might be explained by a variability in symptom experience as described by Gelhorn et al.16 They

found that not all patients experience all symptoms and there was variability in how patients

experienced symptoms within and among days.

228

Chapter ten

The statistically significant but lack of clinically relevant improvement in joint function (WOMAC)

could be explained by the destruction the disease already caused, or by the small number of

questionnaires left after exclusion of many patients to optimize the homogeneity of the patient

group. The lack of disease specific instruments to evaluate adequate PROMs for TGCT, may have

led to underreporting disease specific issues.

SF-36 was developed to get more general insight into patients’ health and as a means of making

comparisons across conditions29. VAS was developed as a pain assessment tool used for cancer

patients19. The WOMAC was originally developed to evaluate the outcome of a total knee

replacement in patients with osteoarthritis.20 SF-36, VAS and WOMAC are a good start in assessing

the patients perspective in TGCT, since they are validated, easy to apply and globally known. These

measures are frequently used for other diseases, allowing to compare TGCT patients with other

patient groups, for example patients with joint replacements for osteoarthrosis30,22, 31. Gelhorn et

al. investigated ‘patient-reported symptoms of TGCT’. They concluded that pain (VAS), swelling,

stiffness and impaired joint function (WOMAC) are important PROMs.

Van der Heijden et al. 15 evaluated 30 patients with therapy-naïve and recurrent diffuse-type TGCT

at a mean of 8 (range 2-32) years after diagnosis. HRQoL impairment (SF-36) was seen in all patients

initially treated with arthroscopic synovectomy (62 range 26-94) and an open synovectomy (80

range 63-98), compared to healthy controls15. The patient population was small and heterogeneous,

in which outcome measures were assessed at different time points after treatment. In the study of

Verspoor at al.2, which experienced similar limitations, HRQoL (SF-36) scores were not significantly

different between localized- and diffuse-type TGCT. However, both patient groups had impaired

HRQoL compared to general population means one the general health subscale. Diffuse patients

also scored significantly lower on other subscales (PF, MH and VT). The current study, with a more

homogenous, larger patient cohort and measurements at categorized time intervals, showed a

similar impairment in therapy-naïve patients on PF preoperatively for both subtypes and up to

6 months postoperatively in diffuse-type patients who generally need more extensive surgery

compared to localized-type TGCT.


229

10

Case series reporting on joint function before treatment often included both subtypes, various

localizations, a mixture of therapy-naïve and recurrent TGCT including multiple treatments15, 27,

32-34. Therefore, it is extremely challenging to perform a meta-analysis to prove treatment effect(s)

in the rare disease TGCT. Through the emergence of systemic treatments for TGCT, attention for

additional outcome measures besides recurrences has been raised, such as HRQoL and joint

function. International cooperation has been initiated, resulting in large registries including QoL

and joint function35. In the recent years targeted therapy has been added to the armamentarium.

At ASCO 2018 results of pexidartinib (PLX3397)12, a selective inhibitor of CSF-1 receptor, KIT,

and FLT3-ITD, were promising in a randomized, placebo controlled, phase 3 study. Pexidartinib

compared to placebo resulted in an significantly improved overall response rate (39.3% vs 0%) and

PROMIS physical function (4.06 vs 0.89), after a median 6 months follow up12. In this study range of

motion, PROMIS physical function, worst stiffness and pain response were secondary endpoints12.

The joint localization of TGCT might influence physical function36, 37. Therefore, a sensitivity analysis

was performed on our patients with TGCT affecting the knee, which showed similar results to our

primary analysis. In a univariate analyses on TGCT locations with recurrent disease as outcome,

Palmerini et al.38 did not find a difference between knees, hips and ankles.

Two crowdsourcing studies39, 40, using an online patient support-group, reported on physical

function and HRQoL in TGCT patients. In patients with diffuse-type TGCT, recurrences requiring

repeated surgery and joint replacement were reported to have a lower HRQoL and functional

outcome39, 40. Because of selection bias, it is possible that severe cases including (additional)

recurrences were more likely to be online to complete the e-survey. However, all studies, including

the current one suggest an impaired effect on HRQoL and function in patients with TGCT. The

challenge remains to find the exact quantification method.

This study has some limitations that need to be discussed. Because of the rarity of TGCT, it

is challenging to perform a prospective study with adequate patient numbers. To reduce

heterogeneity of the patient group, we chose to exclude recurrent patients, at the expense of

decreasing patient numbers. Still, heterogeneity in severity and duration of illness remained.

230

Chapter ten

Selection bias should be taken into account, because this study only contains patients from two

tertiary Dutch referral centres. Overrepresentation of extensive disease, could have resulted in an

overestimation of the impact on HRQoL and joint function. Also, patients with complaints more

often visit the outpatient clinic completing questionnaires. These patients might have more

extended, metastatic, disease. By excluding patients with recurrent TGCT, this possible bias was

reduced. On the contrary, patients who do well, like localized-type TGCT patients, were discharged

early reducing their follow up time and number of questionnaires.

It should be noticed that HRQoL and function scores were taken at variable points after treatment

for individual patients, which reduced numbers at some specific time points. Not all patients

had preoperatively and postoperative available measures, causing an increase in the range of

these outcome measures. Furthermore, it is preferred to adjust SF-36 measures for age, because

of physiologically declined HRQoL and joint function decrease in ageing18, 41. In the current study

correction for age could not be achieved by differences in ages per time interval and the age

distribution within time intervals.

Patients with localized-type TGCT generally do not have a high burden of their disease. The

question is whether PROMs are essential in patients with localized disease, who can generally be

treated curatively with a radical excision and are not eligible for systemic therapy. To date, surgical

resection remains the treatment of choice for TGCT, but is associated with high recurrence rates and

multiple additional surgeries in diffuse-type disease.10 The balance between increased morbidity

of multiple or invasive surgeries15, 42, alternative therapeutic options, and daily symptoms of the

tumour is challenging. A more aggressive resection or other multimodality treatments, such as

external beam radiation therapy, may adversely affect QoL, joint function and the development of

osteoarthrosis, which are, given the young adult age group, factors of major importance2, 38. Use

of a control group and of specific and validated PROMs will better document treatment-induced

symptomatic, functional and economic (back to work) consequences of these treatments16.

When systemic treatments show tumour growth arrest and symptomatic improvements, a less

invasive approach would be justified11. The recent studies on targeted therapy used a control

group and as secondary outcome measure PROMIS physical function12.


231

10

These measures are critical endpoints in demonstrating clinical relevance and impact of treatments

for benign diseases in which death is no outcome variable.16 Clinical benefit necessitates objective

measures to correlate with tumour reduction. When significant changes in TGCT specific

developed outcome measures are found, one should try to specify if this is the consequence of the

disease itself, of the ‘multiple’ treatment(s) received, or of other factors, such as comorbidities, the

knowledge of having a tumour or issues not related to disease.

conclusion

Patients report a significant better HRQoL after surgery in TGCT whereas joint function showed

a trend towards improvement. Pain scores –which vary hugely between patients and in patients

over time- did not improve. A disease specific patient-reported outcome measure would help to

decipher impact of TGCT on patients’ daily life and functioning in more detail.

232

Chapter ten

references

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da

ily

liv

ing

the patient perspective on

the impact of tenosynovial giant

cell tumours on daily living

chap

ter

elev

en

M.J.L. Mastboom1, R. Planje1, M.A.J. van de Sande1

Interact J Med Res. 2018 Feb 23;7(1):e4.

crowdsourcing study on physical function and quality of life

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Impact of tenosynovial giant cell tumours on daily living

abstract

Background

Tenosynovial Giant Cell Tumour (TGCT) is a rare, benign lesion affecting the synovial lining of

joints, bursae, and tendon sheaths. It is generally characterized as a locally aggressive and often

recurring tumour. A distinction is made between localized- and diffuse-type. The impact of TGCT

on daily living is currently ill-described.

Objective

The aim of this crowdsourcing study was to evaluate the impact of TGCT on physical function,

daily activities, societal participation (work, sports, and hobbies), and overall quality of life from

a patient perspective. The secondary aim was to define risk factors for deteriorated outcome in

TGCT.

Methods

Members of the largest known TGCT Facebook community, PVNS is Pants!!, were invited to an

e-survey, partially consisting of validated questionnaires, for 6 months. To confirm disease

presence and TGCT-type, patients were requested to share histological or radiological proof of

TGCT. Unpaired t tests and chi-square tests were used to compare groups with and without proof

and to define risk factors for deteriorated outcome.

Results

Three hundred thirty-seven questionnaires, originating from 30 countries, were completed.

Median age at diagnosis was 33 (interquartile range [IQR]=25-42) years, majority was female (79.8%

[269/337]), diffuse TGCT (70.3% [237/337]), and affected lower extremities (knee 70.9% [239/337]

and hip 9.5% [32/337]). In 299 lower-extremity TGCT patients (32.4% [97/299]) with disease

confirmation, recurrence rate was 36% and 69.5% in localized and diffuse type, respectively. For

both types, pain and swelling decreased after treatment; in contrast, stiffness and range of motion

worsened. Patients were limited in their employment (localized 13% [8/61]; diffuse 11.0% [21/191])

and sport-activities (localized 58% [40/69]; diffuse 63.9% [147/230]). Compared with general US

population, all patients showed lower Patient-Reported Outcomes Measurements Information

System-Physical Function (PROMIS-PF), Short Form-12 (SF-12), and EuroQoL 5 Dimensions 5

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Levels (EQ5D-5L) scores, considered clinically relevant, according to estimated minimal important

difference (MID). Diffuse versus localized type scored almost 0.5 standard deviation lower for

PROMIS-PF (P<.001) and demonstrated a utility score of 5% lower for EQ-5D-5L (P=.03). In localized

TGCT, recurrent disease and ≥2 surgeries negatively influenced scores of Visual Analog Scale (VAS)-

pain/stiffness, SF-12, and EQ-5D-5L (P<.05). In diffuse type, recurrence resulted in lower score for

VAS, PROMIS-PF, SF-12, and EQ-5D-5L (P<.05). In both types, patients with treatment ≤1year had

significantly lower SF-12.

Conclusions

TGCT has a major impact on daily living in a relatively young and working population. Patients

with diffuse type, recurrent disease, and ≥2 surgeries represent lowest functional and quality of

life outcomes. Physicians should be aware that TGCT patients frequently continue to experience

declined health-related quality of life and physical function and often remain limited in daily life,

even after treatment(s).

introduction

Tenosynovial Giant Cell Tumour (TGCT), previously pigmented villonodular synovitis (PVNS), is a rare,

proliferative neoplasm affecting the synovial lining of joints, bursae, and tendons sheaths. According

to growth pattern, a radiological distinction is made between a well-circumscribed lesion (localized

type) and a locally more aggressive lesion (diffuse type)1, 2. The incidence rate reveals its rarity: for

localized type (excluding digits), 10.2 per million person-years and for diffuse type, 4.1 per million

person-years. TGCT is a monoarticular disease, concerning large joints, typically about the knee: 46%

in localized-type and 64% to 75% in diffuse-type. Male-female ratio is about 1:1.5 for both types, with

a median age at the time of TGCT diagnosis of 30 to 50 years1-3. Most common initial symptoms are

pain, stiffness, and swelling. Additional symptoms might be limited range of motion, instability, giving

way, and locking complaints4. Due to these unspecific signs and the rarity of the disease, patients

frequently experience a delay of years in diagnosis3, 5, 6. To treat these symptoms, current treatment

of choice is surgical excision, either by arthroscopic or open synovectomy7. After surgical resection,

high recurrence rates are known, with the localized type up to 50% and the diffuse type up to 92%6.

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Once TGCT is diagnosed, a high health care burden is identified with a significant increase in

health care costs, ambulatory expenses, and physical therapy8. In describing treatment benefits

and standard oncologic end points, patient-reported outcome instruments are increasingly used.

Visual Analog Scale (VAS) for worst pain-stiffness and Patient-Reported Outcomes Measurement

Information System- Physical Function (PROMIS-PF) questionnaires were identified as most valuable

measures for TGCT symptoms in a relatively small TGCT patient cohort (n=22)4.

The impact of TGCT symptoms following surgery(s) and recurrences on daily living, sports, and

work activities is currently ill-described. Although TGCT is not considered lethal, this tumour is

hypothesized to have major impact on daily living. Especially diffuse disease is notorious for its

negative influence on both local recurrence risk and functional outcome9.

Use of an e-survey is a unique possibility to reach a large elusive TGCT population and to globally

evaluate impact of TGCT on patients’ daily life. This crowdsourcing study evaluates effect of TGCT on

physical function, daily activities, societal participation (work, sports, and hobbies), and overall quality of

life from a patient perspective. Secondary aim is to define risk factors for deteriorated outcome in TGCT.

methods

Study design

This cross-sectional crowdsourcing study was performed at Leiden University Medical Centre,

Leiden, The Netherlands, in accordance with good clinical practice [the Declaration of Helsinki

(2000)]. This study was conducted from December 2016 until end of May 2017 (6 months), using

the largest known online TGCT community on Facebook, PVNS is Pants!!, to gather participants for

the Web-based questionnaire. The study was conducted conforming to the Checklist for Reporting

Results of Internet E-Surveys (CHERRIES), the checklist focusing on Web-based surveys10 (Appendix

1). NetQuestionnaire (NetQ) was used to complete the TGCT questionnaire. NetQ is a professional

Web-survey software, approved for (bio)medical research and supported by the Leiden University

Medical Centre (LUMC). Respondents were able to review and change their answers before

submitting.

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Patients and Recruitment

Members of PVNS is Pants!! were requested to participate in our international crowdsourcing

study “Evaluation of Tenosynovial Giant Cell Tumour on daily living” (Appendix 2). At the time of

writing (December, 2016), this closed Facebook community contained 2179 members. A patient-

friendly TGCT-research-related message was posted in the Facebook community every 4 weeks

to encourage TGCT patients to complete the questionnaire. Additional study updates and easily

understandable information on TGCT were posted on the page of a newly designed TGCT study

Facebook account11.

All members of the Facebook community had access to the questionnaire. Solely patients

with TGCT diagnosis were requested to participate in this study. To achieve a higher level of

evidence, confirmation of TGCT (histological or radiological) was requested after completing the

questionnaire. Sending (anonymized) medical reports to our protected email account was highly

desirable but left to the discretion of the participant.

Members of Facebook community PVNS is Pants!! have been notified that (research-minded)

doctors are members of this closed Facebook community for several years. Participation in this

study was voluntary, and no incentives were offered. Informed consent was given by completing

the survey. This study was approved by the Institutional Review Board (CME) from our institution

(registration number P16.232, December 5, 2016).

Unique site visitors were determined by Internet protocol (IP) addresses. When duplicate entries

were detected, the most recent one was included in the analyses. All password-protected

documents were only accessible to TGCT researchers and saved on the secured departmental

drive of our hospital. Data of participants were anonymized when medical proof was received or

when the participant did not respond to our third request for medical confirmation. To ascertain

TGCT diagnosis and TGCT type, all medical reports were verified by 2 TGCT researchers (MJLM, RP).

When in disagreement, medical reports were checked by the senior orthopaedic surgeon (MAJS)

for final conclusion.

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Questionnaire

On the very active Facebook community PVNS is Pants!!, several patient-initiated questionnaires

and polls were performed, for instance, about treatments, coping strategies, daily limitations, and

emotional struggles. Members expressed their desire for studies regarding these topics, since the

majority of TGCT studies concern physical function and recurrent disease as outcome parameters.

Therefore, a Web-based questionnaire, using mostly validated questionnaires, was composed to

describe impact of TGCT on health-related outcome and daily living from a patient perspective. A

prerequisite was that the questionnaire would be relevant for the heterogeneous TGCT population:

for different large joints, different ages, males or females, localized or diffuse type, and for patients

at different treatment stages.

To assess relevance and completeness of our questionnaire, a pilot test with the composed

questionnaire was performed. One dedicated orthopaedic oncologic surgeon (MAJS), 2 medical

doctors (MJLM, RP), and 5 TGCT patients in our outpatient clinic, all fluent in written and spoken English

language, tested the e-survey. Validated questionnaires were used as published by the owners. After

the pilot test, a few nonvalidated questions were added or rephrased (Appendix 3).

Nonvalidated questions concerned patient and tumour characteristics, medical history, TGCT symptoms,

performed treatments, recurrences, employment status, sports, and number of visits to general

practitioner and orthopaedic surgeon. The majority of questions had a multiple-choice character,

including a not applicable or other answer option. The exact number of nonvalidated questions

depended on given answers. For instance, patients with an extensive TGCT-related history were asked

additional questions on their history, in contrast to the patients awaiting their initial treatment.

Validated questionnaires on physical function and quality of life included: VAS for worst pain and

stiffness in the last 24 hours, PROMIS-PF items, Short Form-12 Health Survey (SF-12), and EuroQoL

EQ-5D-5L (EQ-5D-5L Descriptive System and EQ-5D-5L VAS). A total of 32 validated questions were

included. VAS for pain and stiffness was used to estimate patient’s pain and stiffness intensity for

the past 24 hours: no pain/stiffness at all (0) and worst pain/stiffness imaginable (10).

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PROMIS-PF instruments were used to measure self-reported capability of physical activities. In

this study, short forms of physical functioning for lower and upper extremity were used with 5

response options: without any difficulty (5), with a little difficulty (4), with some difficulty (3), with

much difficulty (2), and unable to do (1). Raw score was calculated by summing up the values of

the response to each question and was converted into a T score by the Assessment Centre from

PROMIS-PF. A mean of a standardized T score of 50 with a standard deviation of 10 reflects the

general US population12.

The SF-12, a generic measure of health status, functioned as a shorter alternative for the SF-36.

Number of answer options differed per question. Physical component summary (PCS) score and

mental component summary (MCS) score were calculated. Similar to PROMIS-PF, the general US

population had a mean of 50 with a standard deviation of 1013.

The EQ-5D-5L is one of the most commonly used generic health status measures in the world.

Its descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain

or discomfort, and anxiety or depression, with the following 5 levels of problems per dimension:

no problems (1), slight problems (2), moderate problems (3), severe problems (4), and extreme

problems (5)14. For each participant, answers per dimension were combined into an EQ-5D-5L

health state. This health state was converted into a single index value (so-called utility score) for

quality of life, by using the Crosswalk Index Value Calculator version 1.0 from the EuroQoL Group15.

Utility scores were measured on an ordinal scale of 0 to 1, with 0 indicating death and 1 indicating

full health16. Crosswalk valuation set for US population was used for all participants, since majority

of the patients originated from the United States (42.7% [144/377]). A specific analysis, called

sensitivity analysis, was performed using the valuation set for UK population, the second largest

patient population (20.2% [68/337]) in this study. Scores calculated with US valuation set were

compared with scores obtained by using UK valuation set to assess representativeness of the

scores from validated questionnaires14 (Appendix 4).

Statistical Analysis

NetQ automatically captured questionnaire answers into an SPSS 23 file. Evaluation of TGCT on

daily living was mainly descriptive.

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Chi-square tests were used to compare patient groups with and without medical proof regarding

gender (male vs female), TGCT localization (knee vs other large lower extremity joints [hip, ankle,

and foot]), initial surgery (arthroscopy vs [one- or two-staged] open synovectomy), recurrence (yes

vs no), total number of surgeries (1 surgery vs ≥2 surgeries), and time since last treatment for TGCT

(≤1 year ago vs >1 year ago) (Appendix 5).

Independent t tests were used to compare the mean age at the time of diagnosis and continuous

scores of validated questionnaires. All reported P values were two-tailed. Statistical significance

level was defined at P<.05.

Effect size, as a quantitative measure of the strength of a phenomenon, was calculated for both

PROMIS-PF and SF-12 scores in localized- and diffuse-type patients, compared with general US

population score. Effect size, or Cohen d, is the ratio of difference between two means divided by

the standard deviation, expressed in standard deviation units. An effect size between 0.2 and 0.5

is considered small, 0.5 and 0.8 medium, and above 0.8 large17.

The minimal important difference (MID), a quality of life measure, represents the smallest

difference or change beyond statistical significance in an outcome measure score that would

be considered clinically relevant by the value patients place on change. MID for EQ-5D-5L Index

Scores is estimated between .037 and .069, based on the simulation-based instrument-defined

MID estimates18. MID for PROMIS-PF was determined by Yost et al. in advanced-stage cancer

patients19. Differences in T scores between 4.0 and 6.0 were considered clinical relevant. MID for

SF-12 PCS and MCS scores were calculated by Díaz-Arribas et al. in >450 patients with low back

pain and were stated at >3.29 for PCS and >3.77 for MCS20.

results

The TGCT questionnaire was initiated by 445 participants within a time frame of 6 months. For the

present analysis, only fully completed, unique questionnaires (337) were included (Figure 1). The

majority of incomplete questionnaires were early dropouts with a great lack of information and

therefore unsuitable for analysis.

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Most patients were female (79.8% [269/337]) and median age at diagnosis was 33 (interquartile

range [IQR]=25-42) years. Patients originated from 30 different countries (United States: 42.7%

[144/337]; United Kingdom: 20.2% [68/337]; and the Netherlands: 12.8% [43/337]). TGCT was

typically located in lower extremities: knee (70.9% [239/337]), hip (9.5% [32/337]), ankle (11.0%

[37/337]), and foot (3.0% [10/337]). Diffuse TGCT was diagnosed in 237 of 337 (70.3%) patients

(Table 1). According to few TGCT patients with TGCT located in the upper extremity, 12 out of 337

patients (3.6%) were excluded for further analyses. Additionally, 26 out of 337 lower-extremity

Figure 1 Flowchart Tenosynovial Giant Cell Tumour (TGCT) questionnaire.

Q: Questionnaires; L: Localized-TGCT; D: Diffuse-TGCT; U: Unknown-type TGCT

455 questionnaires

excluded14 double Q

104 incomplete Q

3 L 7 D 2 U 230 D

299 L/D-TGCTof lower-extremities

337 fully completed,unique Q

325 lower-extremity

69 L 26 U

12 upper-extremity

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Table 1 Patient and tumour characteristics (N=337)

Characteristics Value

Age at time of questionnaire (years), median (IQRa) 41 (32-50)

Age at time of TGCT diagnosis (years), median (IQR) 33 (25-42)

Total, N (%) 337 (100)

Gender, n (%)

Male 68 (20.2)

Female 269 (79.8)

Country of residence, n (%)

United States of America 144 (42.7)

United Kingdom 68 (20.2)

The Netherlands 43 (12.8)

Australia 22 (6.5)

Canada 14 (4.2)

Other 46 (13.6)

TGCTb localization, n (%)

Knee 239 (70.9)

Hip 32 (9.5)

Ankle 37 (11.0)

Foot 10 (3.0)

Shoulder 4 (1.2)

Elbow 6 (1.8)

Wrist 2 (0.6)

Otherc 7 (2.1)

TGCT type, n (%)

Localized 72 (21.4)

Diffuse 237 (70.3)

Unknown 28 (8.3)

aIQR: interquartile range (25-75%)bTGCT: tenosynovial giant cell tumour

cOther included multiple TGCT locations (all in lower extremity)

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patients (7.7%) with unknown TGCT type were also excluded (Figure 1). Questionnaires of 299

lower-extremity patients with localized or diffuse TGCT were analysed.

Disease Confirmation

Confirmation of TGCT was sent by 32.4% (97/299) of lower-extremity participants. In 81% (78/97)

TGCT type was in concordance with questionnaire answer, in 16/97 (16%) medical reports TGCT

type did not match the answer and was therefore adjusted according to the report and 3/97 (3%)

patients answered TGCT type unknown and TGCT type was added in consistence with the report.

No important differences between patients with and without medical proof were detected

(Appendix 5), neither for localized or diffuse type separately. Therefore, patients with medical proof

were considered representative for the entire study population and additional analyses were

performed for the entire patient group.

Medical History and Tenosynovial Giant Cell Tumour Symptoms

5/69 (7%) and 29/230 (12.6%) in localized- and diffuse-type patients, respectively, had an

autoimmune disease, mostly diabetes mellitus type I, Hashimoto, psoriasis, and thyroid disease.

In all, 22/69 (32%) of localized-type and 70/230 (30.4%) of diffuse-type patients experienced a

Table 2 Initial and current symptoms for localized and diffuse Tenosynovial Giant Cell Tumour

(TGCT) (n=337)

TGCTa-related symptom Localized TGCT (n=69) Diffuse TGCT (n=230)

Initial, n (%) Current, n (%) Initial, n (%) Current, n (%)

Pain 57 (83) 47 (68) 186 (80.9) 170 (73.9)

Swelling 53 (77) 29 (42) 190 (82.6) 139 (60.4)

Stiffness 38 (55) 41 (59) 128 (55.7) 148 (64.3)

Limited range of motion 38 (55) 29 (42) 140 (60.9) 149 (64.8)

aTGCT: tenosynovial giant cell tumour

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trauma at TGCT-affected joint, before diagnosis; sports injuries or fall incidents leading to a sprain

or rupture. In all, 5/69 (7%) and 12/230 (5.2%) of patients in localized and diffuse TGCT had surgery

of the affected joint before TGCT diagnosis, respectively, for example, meniscus or anterior cruciate

ligament (ACL) reconstructions. In all, 6/230 (2.6%) of diffuse-type participants experienced both

trauma and surgery before TGCT diagnosis.

Majority of patients (92.6% [277/299]) were treated for TGCT. For both types, pain and swelling

improved compared with initial situation. After treatment, more patients reported stiffness and

Table 3 Treatment characteristics of 277 treated tenosynovial giant cell tumour (TGCT) patients

Treatment Localized TGCTa (n=67)

Diffuse TGCT (n=210)

Initial surgery, n (%)

Arthroscopic synovectomy 38 (57) 113 (53.8)

Open synovectomy (one- or two-staged) 26 (39) 90 (42.9)

Combined arthroscopic/open synovectomy 3 (4) 0 (0.0)

Total joint replacement/(tumour) prosthesis 0 (0) 5 (2.4)

Amputation 0 (0) 2 (1.0)

Adjuvant therapy, n (%) 5 (7) 53 (25.2)

Radiotherapy 4 (6) 18 (8.6)

90-Yttrium 1 (1) 14 (6.7)

Systemic 0 (0) 15 (7.1)

Otherb 0 (0) 6 (2.9)

Recurrent disease, n (%) 24 (36) 146 (69.5)

Additional surgery, n (%) 23 (34) 125 (59.5)

Arthroscopic synovectomy 7 (10) 32 (15.2)

Open synovectomy (one- or two-staged) 10 (15) 74 (35.2)

Combined arthroscopic/open synovectomy 1 (1) 4 (1.9)

Total joint replacement/(tumour) prosthesis 2 (3) 12 (5.7)

Amputation 3 (4) 3 (1.4)

aTGCT: tenosynovial giant cell tumourbOther adjuvant therapies were cryosurgery, burning tools, steroid injections,

or combination of multiple adjuvant therapies

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limited range of motion (Table 2). A minority of the patients (<6%) currently experienced additional

symptoms, including instability, buckling, hyperextension and/or hypermobility, clicking or

locking or popping of joint, numbness, electric shocks, tingling, dull ache, heat of the affected

joint, or hematoma.

Treatment(s)

Most performed initial surgery was arthroscopic synovectomy (57% [38/67] localized, 53.8%

[113/210] diffuse) and open synovectomy, one- or two-staged (39% [26/67] localized, 42.9% [90/210]

diffuse). In all, 5/67 (7%) localized-type and 53/210 (25.2%) diffuse-type patients had adjuvant

therapies after initial surgery, mainly radiotherapy and 90-Yttrium. In all, 24/67 (36%) of localized

type had recurrent disease after 1.5 (range 1-6) years, in contrast to 146/210 (69.5%) of diffuse type

after 2.2 (range 1-23) years (table 3). Additional surgery was performed in 23/67 (34%) of localized

type and 125/210 (59.5%) of diffuse type, predominantly open synovectomy (one- or two-staged).

Impact of Tenosynovial Giant Cell Tumour on Daily Life

Due to TGCT, 8/61 (13%) and 21/191 (11.0%) of working population in localized and diffuse TGCT,

respectively, was currently not able to (fully) perform their employment. Of these patients, 4/8 (50%)

localized patients and 17/21 (81%) diffuse patients had recurrent disease. Majority of patients, 40/69

(58%) of localized and 147/230 (63.9%) of diffuse type, were unable to perform sport activities. In

these patients, recurrent disease presented in 15/40 (38%) of localized type and 94/147 (63.9%)

of diffuse type. Disease burden was estimated by mean number of visits to general practitioner

(5.6 [range 1-50] visits for localized type, 7.1 [range 1-60] visits for diffuse type), and orthopaedic

surgeon (8.3 [range 1-97] visits for localized type, 11.9 [range 1-100] visits for diffuse type). Results

of validated questionnaires are shown in Table 4 (localized vs diffuse type), Table 5 (localized type),

and Table 6 (diffuse type). Results with positive association are described in the text.

Worst Pain and Stiffness in Last 24 Hours: Visual Analog Scale Score

For localized type, best VAS pain score was 2.76 and VAS stiffness score was 2.80. In diffuse type,

best scores for pain and stiffness were 3.04 and 3.08, respectively. Patients with recurrence of TGCT

had deteriorated VAS score for pain and stiffness (P=.01 localized type and P<.001 diffuse type). In

localized type, patients with ≥2 surgeries had higher VAS score for pain (P=.02) and stiffness (P=.01).

249

11


Tabl

e 4

Ris

k fa

ctor

com

paris

on o

f 69

loca

lized

ver

sus

230

diffu

se te

nosy

novi

al g

iant

cel

l tum

our (

TGC

T) o

f low

er e

xtre

miti

es

TGCT

a -typ

e

Wor

st p

ain

VASb s

core

, 0

best

sco

re a

nd

10 w

orst

sco

re

Wor

st s

tiffne

ss

VAS

scor

e, 0

be

st s

core

and

10

wor

st s

core

PRO

MIS

-PFc T

sco

re,

mea

n 50

(SD

10)

, MID

d 4.

0–6.

0

SF-1

2e , PCS

f sco

re, m

ean

50 (S

D 1

0), M

ID >3

.29

SF-1

2, M

CSg

scor

e, m

ean

50 (S

D 1

0), M

ID >3

.77

EQ-5

D-5

L D

Sh

utili

ty s

core

, 0

deat

h an

d 1

full

heal

th, M

ID

.037

–.06

9

Mea

nPi

Mea

nPi

Mea

nd j

PiM

ean

d jPi

Mea

nd j

PiM

ean

Pi

Loca

lized

3.36

.24

3.46

.14

44.5

0.55

<.00

140

.50.

95.0

847

.50.

25.4

00.

76.0

3

Diff

use

3.79

4.01

41.3

0.87

38.1

1.19

46.3

0.38

0.72

a TGC

T: te

nosy

novi

al g

iant

cel

l tum

our

b VAS:

Vis

ual A

nalo

gue

Scal

ec PR

OM

IS-P

F: P

atie

nt-R

epor

ted

Out

com

es M

easu

rem

ent I

nfor

mat

ion

Syst

em-P

hysi

cal F

unct

ioni

ngd M

ID: m

inim

al im

port

ant d

iffer

ence

repr

esen

ts th

e sm

alle

st d

iffer

ence

or c

hang

e be

yond

sta

tistic

al s

igni

fican

ce in

an

outc

ome

mea

sure

sco

re th

at w

ould

be

cons

ider

ed im

port

ant b

y th

e va

lue

patie

nts

plac

e on

cha

nge18

-20

e SF: S

hort

-For

mf PC

S: p

hysi

cal c

ompo

nent

sum

mar

yg M

CS: m

enta

l com

pone

nt s

umm

ary

h DS:

des

crip

tive

syst

emi P:

P v

alue

j d: C

ohen

d o

r effe

ct s

ize,

ratio

of d

iffer

ence

bet

wee

n 2

mea

ns d

ivid

ed b

y th

e st

anda

rd d

evia

tion

250

Chapter eleven

Table 5

Risk factor comparison of 69 localized tenosynovial giant cell tumour (TGCT) of lower extremities.

Risk-factors

Worst pain VASa score, 0 best score

and 10 worst score

Worst stiffness

VAS score, 0 best

score and 10 worst

score

PROMIS-PFb T

score, mean 50 (SD 10),

MIDc 4.0-6.0

SF-12d, PCSe score,

mean 50 (SD 10),

MID >3.29

SF-12, MCSf score,

mean 50 (SD 10),

MID >3.77

EQ-5D-5L DSg utility

score, 0 death

and 1 full health, MID

.037-.069

score Pi score Pi score Pi score Pi score Pi score Pi

Gender

Male (n=14) 2.93 .53 3.29 .79 48.5 .04 43.3 .23 49.4 .42 .81 .18

Female (n=55) 3.47 3.51 43.5 39.8 47.0 .75

Age of diagnosis

<35 years (n=36) 3.36 .997 3.39 .82 44.1 .63 40.1 .74 45.4 .07 .76 .95

≥35 years (n=33) 3.36 3.55 45.0 40.9 49.8 .77

TGCT localization

Knee (n=53) 3.04 .08 3.13 .07 44.2 .57 41.0 .43 47.2 .63 .77 .41

Hip, ankle, foot, other (n=16) 4.44 4.56 45.5 38.8 48.6 .74

Initial surgery

Arthroscopy (n=38) 3.45 .58 3.26 .63 44.2 .52 40.7 .96 47.2 .73 .76 .92

Open surgeryh (n=26) 3.04 3.62 45.6 40.8 48.0 .77

Recurrence

Yes (n=24) 4.50 .01 4.71 .01 42.8 .20 38.3 .17 45.7 .27 .70 .01

No (n=45) 2.76 2.80 45.4 41.7 48.5 .80

Total no. of surgeries

1 surgery (n=44) 2.77 .02 2.86 .01 45.4 .20 42.2 .03 48.4 .19 .79 .02

≥2 surgeries (n=23) 4.48 4.65 42.6 36.7 45.0 .71

Last treatment for TGCT

≤1 year ago (n=31) 3.77 .26 3.81 .38 42.4 .06 37.6 .04 46.0 .34 .74 .29

>1 year ago (n=36) 3.00 3.19 46.1 42.6 48.3 .78

aVAS: Visual Analogue Scale. bPROMIS-PF: Patient-Reported Outcomes Measurement Information System-Physical Functioning. cMID: minimal important difference represents the smallest difference or change beyond statistical significance in an outcome measure score that would be considered important by the value patients place on change18-20 . dSF: Short-Form. ePCS: physical component summary. fMCS: mental component summary. gDS: descriptive system. hOne- or two staged open synovectomy. iP: P value

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11


Table 6

Risk factor comparison of 230 diffuse tenosynovial giant cell tumour (TGCT) of lower extremities.

Risk-factors

Worst pain VASa score, 0 best score

and 10 worst score

Worst stiffness

VAS score, 0 best

score and 10 worst

score

PROMIS-PFb T

score, mean 50 (SD 10),

MIDc

4.0-6.0

SF-12d, PCSe score,

mean 50 (SD 10),

MID >3.29

SF-12, MCSf score,

mean 50 (SD 10),

MID >3.77

EQ-5D-5L DSg utility

score, 0 death

and 1 full health, MID

.037-.069

score Pi score Pi score Pi score Pi score Pi score Pi

Gender

Male (n=51) 3.63 .70 4.13 .71 42.2 .23 39.9 .11 49.0 .04 .75 .17

Female (n=179) 3.84 3.98 41.0 37.5 45.6 .71

Age of diagnosis

<35 years (n=119) 3.70 .58 3.74 .09 42.1 .07 39.2 .07 46.9 .38 .73 .22

≥35 years (n=109) 3.89 4.32 40.4 36.8 45.6 .71

TGCT localization

Knee (n=170) 3.78 .93 3.92 .07 41.6 .29 38.1 .99 46.3 .98 .73 .40

Hip, ankle, foot, other(n=60) 3.82 4.55 40.5 38.1 46.3 .71

Initial surgery

Arthroscopy (n=113) 3.93 .82 4.19 .64 41.6 .66 38.3 .86 45.6 .64 .73 .25

Open surgeryh (n=190) 3.84 4.01 41.2 38.0 46.4 .70

Recurrence

Yes (n=146) 4.23 <.001 4.55 <.001 40.5 .02 37.7 .49 45.1 .04 .70 .02

No (n=84) 3.04 3.08 42.7 38.7 48.2 .75

Total no. of surgeries

1 surgery (n=86) 3.79 .69 3.74 .09 42.0 .20 38.7 .48 46.1 .89 .73 .44

≥2 surgeries (n=124) 3.94 4.38 40.8 37.7 46.3 .71

Last treatment for TGCT

≤1 year ago (n=72) 4.10 .37 4.35 .37 40.4 .17 35.4 .01 45.6 .59 .70 .17

>1 year ago (n=138) 3.76 4.00 41.8 39.5 46.5 .73

aVAS: Visual Analogue Scale. bPROMIS-PF: Patient-Reported Outcomes Measurement Information System-Physical Functioning. cMID: minimal important difference represents the smallest difference or change beyond statistical significance in an outcome measure score that would be considered important by the value patients place on change18-20. dSF: Short-Form. ePCS: physical component summary. fMCS: mental component summary. gDS: descriptive system. hOne- or two staged open synovectomy. iP: P value

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Chapter eleven

Patient-Reported Outcomes Measurements Information System-Physical Function: T Score

All TGCT patients had clinically relevant impaired T scores (44.5 and 41.3 for localized and diffuse

type, respectively) compared with the general US population (T score of 50). Corresponding effect

size was medium for localized type (d=0.55) and large for diffuse type (d=0.87). When comparing

both types, diffuse-type patients scored lower (P<.001). In localized type, female patients scored

lower (P=.04). Diffuse-type recurrent patients had decreased scores (P=.02).

Short Form-12 Health Survey: Physical and Mental Component Summary Score

In comparison with general US population (score of 50), both types had impaired PCS (40.5 localized

and 38.1 diffuse type) and MSC scores (47.5 localized and 46.3 diffuse type). In all patients in all

compared groups, PCS score was clinically relevant declined, in contrast to MCS score which did

not transcend the MID threshold in majority of patient groups. A large effect size was calculated

for mean PCS scores (0.95 and 1.19 for localized and diffuse type, respectively) and a medium

effect size (0.25 and 0.38 for localized and diffuse type, respectively) for MCS scores. In localized

type, higher number of surgeries (≥2) affected PCS score negatively (P=.03). Localized- and diffuse-

type patients who underwent treatment for TGCT ≤1 year ago, showed lower PCS score (P=.04

localized, P=.01 diffuse). In diffuse type, female patients demonstrated a decreased MCS score

(P=.04), as well as patients with recurrence of TGCT (P=.04).

EuroQoL 5 Dimensions 5 Levels Health Questionnaire: Index Value

All patients, in all groups (Tables 4-6), presented declined EQ5D-5L utility scores compared with

full health (1), and all scores transcended MID threshold. Overall, utility score was lower in diffuse

patients compared with localized patients (P=.03). In localized type, participants with recurrence

of TGCT and ≥2 surgeries scored lower (P=.01 and P=.02, respectively). Similarly, diffuse patients

with recurrence had decreased scores (P=.02). Median health question VAS score was 75 (IQR 65-

85) for localized and 75 (IQR 56.5-85) for diffuse type. No differences between scores calculated

with US and UK valuation sets were detected in sensitivity analysis (Appendix 4).

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11


discussion

Principal Findings

The name of the largest online community of patients with TGCT, PVNS is pants!!, suggests impact

on quality of life. One of the community members motivated the name: “Pants is British slang for

crap or garbage.” To date, it is unknown what the effect of TGCT on daily living is. A questionnaire

was composed in consultation with TGCT patients to determine functional, socioeconomic, and

health burden for TGCT patients. We intended to evaluate TGCT in the real world and concluded

that TGCTs have a large impact on daily living, with declined health-related quality of life and

limitations in daily activities, sports, work, and hobbies: especially the diffuse type of lower

extremities and recurrent disease including multiple surgeries.

Limitations

The most important limitation to this study is selection bias. By using crowdsourcing to gather data,

it is likely to have a higher number of patients with severe or recurrent diseases21. Consequently,

when extrapolating these results to generally described populations of TGCT patients in literature,

care should be taken not to overestimate the decreased physical function and additional

socioeconomic limitations. TGCT usually affects young adults. Since younger patients are more

likely to be on the World Wide Web, and our included patient population had a median age of

33 (25-42) years at time of diagnosis, also in concordance with the WHO classification1, 2 and

Mastboom et al.3, we considered our participants representative for the heterogeneous disease

TGCT. Additionally, the CHERRIES was completed. This checklist provides an understanding of the

sample (self-)selection and its possible differences from a representative sample10 (Appendix 1).

An additional limitation to this study is that patients in different stages of different treatments

were included. To assess comparability within study population, we compared patients who had

treatment less than a year ago with performed treatment over a year ago. No positive associations

were discovered, except for the SF-12 PCS score in both types. This underlines the postoperative

limitations during the first year of follow-up after treatment. As we set out to evaluate impact of

TGCT on daily living in the real world heterogeneous TGCT population, the inclusion of patients

in different treatment stages matched intention of our study. Furthermore, a known disadvantage

of quality of life questionnaires (eg, SF-12) is the generalizability of the questions. Impaired

overall quality of life could be attributed to TGCT but also to additional physical abnormalities or

254

Chapter eleven

psychological problems. Also questionnaires may be completed by patients that have been ill-

informed on their disease. In all, 28 patients filled out unknown type of TGCT, and 16% of patients

who confirmed TGCT with medical proof filled out localized TGCT instead of diffuse TGCT or

vice versa. Undeniably, differentiating in localized and diffuse TGCT is challenging even for (un)

specialized physicians. The relatively high recurrence rate in this study could also be reflected by

unawareness of disease specifics. Recurrence rates in our study were 36% and 70% for localized

and diffuse type, compared with on average 4% to 6% (up to a maximum of 50%) and 14% to 40%

(up to a maximum of 92%) according to van der Heijden et al.6, respectively. It is conceivable that

residual disease or clinical symptoms were filled out as recurrent disease.

The use of self-reported questionnaires harbours the risk of incorrectly answered questions. One

could argue that all patients should have been analysed together, not subdividing into localized

and diffuse type. However, differences between two types are major, and therefore separate

analyses were necessary for a realistic view of impact of TGCT on daily living.

Crowdsourcing

The presumed definition of crowdsourcing is the practice of obtaining services, ideas, or content

by collecting contributions from a comprehensive group from an online community rather

than from traditional data suppliers9. However, the exact definition for crowdsourcing remains

controversial, as 40 definitions originating from 32 unique articles, published between 2006 and

2011, were described by Estellés-Arolas22. It is therefore challenging to well define crowdsourcing

coherently. After analyses of the 40 (sometimes contrasting) definitions, 8 characteristics common

to any given crowdsourcing initiative were found: the crowd, the task at hand, the recompense

obtained, the crowdsourcer or initiator of the crowdsourcing activity, what is obtained by them

following the crowdsourcing process, the type of process, the call to participate, and the medium.

First, in our study, the crowd is presented by patients with TGCT (preferably confirmed by medical

reports). Second, the task at hand is completing a questionnaire about the effect of TGCT on

daily living. Third, participating in this study was voluntary, therefore no recompenses were

offered. Fourth, the initiators of this study are members of the Facebook group PVNS is Pants!!

accompanied with the executors, known as the authors of this paper. Fifth, the researchers and

subsequently the participants and TGCT patients gain more knowledge on the impact of TGCT on

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11


daily living. Sixth, the type of process is an evaluation process, aiming to evaluate effect of TGCT on

daily living. Seventh, all patients with TGCT, fluent in English language, were invited to complete

the questionnaire. Lastly, the medium Facebook was used to broadcast the questionnaire.

Facebook is the best applicable social network site for survey research, because it is continuously

growing, internationally known and exceeds 2 billion users globally (June 2017). The Facebook

community PVNS is Pants!!, created in 2009, is the largest TGCT online support group and mainly

consists citizens of the United States. On this very active, closed Facebook community, patients are

daily updating experiences on their disease, ask for advice from fellow TGCT patients, and comment

on other posts to provide their knowledge or sympathy. By actively posting and commenting on

research proposals, patients expressed their willingness to participate in research on TGCT. From

these posts, we learned that adequate patient information on TGCT is lacking. Our crowdsourcing

study stimulated patients’ involvement in research and was an opportunity to align research

questions with the public’s interest23, 24. TGCT is a rare disease and time to definitive diagnosis is

prolonged due to unspecific symptoms and unfamiliarity of the disease5. A challenge in studying

a rare disease is the lack of big data. Crowdsourcing is an effective and low-cost alternative to

traditional methods of participant recruitment due to the possibility to reach large groups of

individuals in a relatively short time frame25. Van der Heijden et al.9 concluded that crowdsourcing

is a promising way for evaluation of rare diseases. Czajka et al.21 used crowdsourcing to efficiently

recruit a global cohort and is the largest study on patients with multiple hereditary exostoses.

Crosier et al.26 used Facebook to recruit patients with auditory hallucinations; within 6 weeks, over

250 patients had completed this survey. Pohlig et al.27 concluded that enrollment of patients in

prospective studies is time-consuming and could be facilitated by use of crowdsourcing.

To obtain a higher level of scientific value, patients were requested for medical proof to

ascertain TGCT diagnosis. To our knowledge, no other crowdsourcing studies considered disease

confirmation. Patient data and outcome for validated questionnaires were comparable for

patients with and without medical proof. Patients were not uniformly diagnosed and treated as

they originated from 30 different countries globally. Neither was distinguished between treatment

in peripheral or tertiary referral centres. Nevertheless, we consider our study group a reflection

of the current worldwide situation and believe that declined impact on daily living is clinically

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Chapter eleven

relevant for all patients. In contrast to malignant diseases, survival rates are not of interest for

TGCT with its benign character. According to high recurrence rates, quality of life (prior and after

treatment) is essential to evaluate.

Patient-Reported Outcome Measures

Patient reported outcome measures (PROMs) are increasingly used in health policy, patient-

centred care, and shared clinical decision making28. In the era of personalized medicine, patient

involvement is increasing in shared decision making for different treatment strategies with

functional outcome and quality of life. In our study, members of the largest online TGCT community

were involved in establishing the questionnaire Evaluation of TGCT on daily living.

Functional outcome and health-related quality of life are only spars reported for TGCT. Four studies

have reported on standardized PROMS4, 9, 29, 30. Currently, validated PROMS for TGCT patients do

not exist. In accordance with Gelhorn et al.4, VAS for worst pain and stiffness and PROMIS-PF

questionnaires were used. Conform van der Heijden et al.9, 29 and Verspoor et al.30, the SF-12, a

quality of life questionnaire, was included, known as the shorter version of the SF-36. One study

identified a high health care burden with a significant increase in health care costs, ambulatory

costs, and physical therapy in 9328 TGCT patients8.

In benign diseases, including TGCT, death is not an outcome variable. Besides tumour reduction,

critical endpoint measures are clinical relevance and impact of treatment. Currently, clinical

TGCT studies lack specific and validated PROMs to document treatment-induced symptomatic,

functional, and economic (back to work) improvement31. To obtain an impression of physical

function and quality of life in TGCT patients, participants in our study were requested to complete

different validated questionnaires. In our experience, PROMIS-PF was most useful in determining

these functional factors. To minimize the multitude of questions and include the most important

components for clinical TGCT studies, we would propose a combination of PROMIS-PF and a short

quality of life questionnaire, for instance EQ5D5L, in clinical practice.

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11


Risk Factors for Deteriorated Outcome

Risk factors for deteriorated outcome in our study were diffuse-type TGCT, recurrent disease,

and ≥2 surgeries performed. This is in concordance with current literature on risk factors for a

high recurrence rate. According to the necessity of mutilating surgeries to treat recurrences, we

considered risk factors for recurrent disease comparable to risk factors for deteriorated outcome.

Higher recurrence rate in diffuse TGCT compared with localized TGCT is exuberant described1, 5-7, 30,

32-34. Bruns et al.34 described 173 patients treated in 10 orthopaedic departments in Germany and

Austria and reported higher recurrence rates in institutions treating less than 20 cases for TGCT, in

diffuse disease, in the hip joint and after arthroscopy. Schwartz et al.35 described 99 patients with TGCT

in the knee, hip, elbow, or shoulder. They concluded that localization in the knee, previous surgical

procedures, and incomplete synovectomy were related significantly to higher number of subsequent

recurrences. On the basis of current literature and to investigate possible risk factors for recurrent

disease thoroughly, gender, age at time of diagnosis, TGCT localization, initial surgery, presence of

recurrence, total number of surgeries, and time since last treatment for TGCT, were compared.

conclusions

TGCTs have major impact on daily living in a relatively young, working population (median age at

diagnosis, 33 years). Majority of symptoms improve after treatment, however, symptoms remain

in about half of the TGCT patients; especially in patients with diffuse type, recurrent disease, and

≥2 surgeries. The high recurrence rate in diffuse TGCT results in clinically important deteriorated

outcome in physical function and health-related quality of life. In preventing recurrent disease, and

its deteriorated outcome, an extensive mutilating surgery might be necessary. Physicians should

be aware that TGCT patients frequently experience symptoms and limitations in daily life and

societal participation (work, sports, and hobbies), even after treatment(s). We deem it important

for future research to evaluate treatment, including its effectiveness on improving quality of

daily living. With this study, we hope to increase knowledge on TGCT among treating physicians,

highlight the importance of quality of life, and to offer research-based information to patients.

Supplementary data

Supplementary data are available in the online version of this article: http://www.i-jmr.org/2018/1/e4

258

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Prevalence, Patient Characteristics, and Recurrence. A Registry-based Cohort Study in Denmark. The Journal of

rheumatology. 2017;44(10):1476-83.

34. Bruns J, Ewerbeck V, Dominkus M, Windhager R, Hassenpflug J, Windhagen H, et al. Pigmented villo-nodular synovitis

and giant-cell tumor of tendon sheaths: a binational retrospective study. Arch Orthop Trauma Surg. 2013;133(8):1047-53.



am

Puta

tio

nlimb amputation

after multiple treatments of

tenosynovial giant cell tumour

chap

ter

twel

ve

M.J.L. Mastboom1, F.G.M. Verspoor2, H. Gelderblom3, M.A.J. van de Sande1

Case Rep Orthop. 2017;7402570.

series of 4 dutch cases

Limb amputation in tenosynovial giant cell tumours

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12

summary

In Tenosynovial Giant Cell Tumours (TGCT), previously named Pigmented Villonodular Synovitis

(PVNS), a distinction is made between a single nodule (localized-type) and multiple nodules

(diffuse-type). Diffuse-type is considered locally aggressive. Onset and extermination of this

orphan disease remain unclear. Surgical resection is the most commonly performed treatment.

Unfortunately, recurrences often occur (up to 92%), necessitating reoperations and adjuvant

treatments. Once all treatments fail or if severe complications occur; limb-amputation may become

unavoidable. We describe four cases of above knee amputation after TGCT diagnosis.

Background

Tenosynovial Giant Cell Tumour (TGCT) is considered an orphan, mono-articular, locally aggressive

neoplasm1. TGCT patients complain of continued pain, swelling and a decreased range of motion

of the affected joint2. Typically, younger patients (below the age of 40 years) are affected. Time

to definitive diagnosis usually takes several years1. TGCT develops along the synovial lining of

joints, tendon sheaths and bursae1, 3. Two extremes along a continuum of one disease process

are described: a single nodule (localized-type) and multiple nodules (diffuse-type)1, 2, 4. These two

subtypes differ in their clinical and radiological presentation, response to treatment and prognosis.

Histologically, no differences are detected1, 5. Exact onset remains unclear. Current findings are

pleading for both a reactive inflammatory disorder and a clonal neoplastic proliferation, provoking

a CSF1 overexpression; suggesting the tumour-landscaping effect6. The localized-type (Giant Cell

Tumour of Tendon Sheath) is defined as a demarcated benign mass, most commonly occurring

in fingers (85%). Lesions are small (between 0.5 and 4 cm), typically lobulated and white to grey

along with yellow and brown areas1, 2, 4. Reported recurrences ensuing surgical treatment are

relatively low: 0-6%4. On the contrary, the diffuse-type (Diffuse-type Giant Cell Tumour (Dt-GCT),

previously named Pigmented VilloNodular Synovitis (PVNS)), shows extensive involvement of the

entire synovial membrane and tends to have the capability to grow infiltrative through adjacent

structures2, 4. Dt-GCT affects mostly weight-bearing joints: predominantly the knee-joint (75%),

followed by the hip-joint (15%). At present, surgery remains the gold standard, while systemic

targeted treatments are only available in trial-settings7. Recurrence rates for Dt-GCT is 14% (up-to

67) after open synovectomy and 40% (up-to 92) after arthroscopic synovectomy4. Recurrent or

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Chapter twelve

resistant disease, frequently necessitate multiple mutilating surgeries, end occasionally inevitably

in total joint arthroplasties8. Once all treatments fail or severe complications occur: limb-amputation

may become unavoidable. To our knowledge, current literature lacks reports of limb-amputation

in TGCT patients, but patient groups often discuss the possibility on online fora (“PVNS is pants”

closed Facebook community; https://www.facebook.com/groups/91851410592/?ref=ts&fref=ts)9.

To underline potentially aggressiveness of TGCT, four patient history scenarios are described.

Case presentation

Case 1

A female, aged 46, was diagnosed with TGCT. Initial TGCT treatment consisted of three arthroscopic

synovectomies. First synovectomy was supplemented with low-dose radiation, consecutive two

synovectomies with intra-articular 90Yttrium. Fourteen years later, an Magnetic Resonance Imaging

(MRI) scan revealed recurrent TGCT, including bone-involvement. A total knee replacement (TKR)

was performed. Four years later, her knee started to hurt and swell again. Infection parameters were

elevated, MRI showed extensive synovitis and a PET-CT showed enhancement around her TKR, suspect

for recurrent TGCT. Her range of motion was impaired, with a flexion-extension of 50-20-0. Twenty-

three years after initial diagnosis, she was referred to our tertiary orthopaedic oncologic centre. TGCT

re-excision was not an option, as a result of extensive tumour growth (Figure 1a, Figure 1b). Imatinib (a

tyrosine kinase inhibitor with activity against CSF1R) was started for four months. Besides the tumour

growing outwards from her operation-scar, a nearby fistula revealed and started leaking. She was

admitted with malaise, fever, elevated infection parameters, a red swollen right leg and not able to

mobilize. During four weeks of admission she was treated with several blood transfusions attributed

to persistent anaemia, intravenous antibiotics and analgesics. After an investigational tyrosine-

kinase-inhibitor (TKI) in compassionate use was started, she was discharged. After a fall, a few days

after she was discharged, her condition worsened. She was readmitted and treated with intravenous

antibiotics for an acute Staphylococcus aureus infection, provoked by TGCT growing outside the

operation scar composing a direct connection to the TKR. To avoid septic shock: an urgent above

knee amputation seemed a live-saving procedure. Within one month, signs of osteomyelitis revealed.

Treatment with debridement, antibiotics and irrigation stabilized the patient. At one year follow-up,

there were no signs of local recurrence or infection and her phantom pain was decreasing.


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Figure 1a Sagittal T1-weighted

MR image, turbo spin echo, after

intravenous contrast injection in

a 69 year old female patient with

recurrent, end stage TGCT on the

right side. Extensive tumour growth

around her total knee replacement

(TKR), involving the entire knee-

joint: anterior and posterior, ranging

from high up supra-patellar pouch

to below tibia-fibular joint, including

bone-involvement.

Figure 1b Sagittal Short-TI Inversion

Recovery metal clear MR image of

the posterior part of the right knee,

revealing extensive tumour growth,

also growing outside the body.

Characteristic TGCT blooming effect

is seen attributed to scattered areas

of low signal intensity, typical for iron

deposition.

a

b

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Chapter twelve

Figure 2a Left knee sagittal

T1-weighted MR image after

intravenous contrast injection with

fat suppression in a 61-year old male

patient with extensive recurrent

Dt-GCT, showing characteristic

blooming effect. a

b

Figure 2b Sagittal turbo-spin echo

proton density-weighted MR image

presents Dt-GCT located intra- and

extra-articular, posterior a large

Baker’s cyst including tumour

involvement.


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12

Case 2

A 63-year old male was referred to our tertiary hospital with recurrent Dt-GCT of his left knee.

Two years prior to referral, Dt-GCT was diagnosed and (partial) arthroscopically removed

elsewhere. MRI showed a diffuse TGCT growth-pattern involving all compartments of the entire

knee-joint, including a Bakers cyst (Figure 2a, Figure 2b). Consequently, a two-staged anterior

and posterior synovectomy in two tempi was performed; macroscopically all pathological tissue

was removed. There was chondromalacia grade 3-4. A few months later, the patient suffered

progressive knee pain again. Recurrent Dt-GCT lesions, including bone-involvement and

progressive osteoarthritis were seen on X-ray and MRI. A transarticular distal femoral resection

and resection of all Dt-GCT tissue was performed. The knee joint was reconstructed using an

EndoProsthetic-Reconstruction (EPR). Thereafter patient’s knee function seemed to improve.

However, several months later, swelling and increasing knee pain developed. C-reactive protein

(CRP) and erythrocyte sedimentation rate were elevated, nevertheless cultures of aspirated

knee fluid were negative. Along with general deterioration of the patient, wound debridement,

antibiotics, irrigation, and retention (DAIR) was performed. Two out of six cultures, showed

coagulase negative staphylococci without a sign of recurrent TGCT. Despite the DAIR procedure,

his EPR had to be replaced with a gentamicin loaded spacer. Because of the difficulty to treat the

low-grade infection, his spacer was replaced with a gentamicin and vancomycin loaded spacer.

Thereafter, patient’s condition improved, his infection parameters declined and cultures of an

open biopsy were negative. The EPR was re-implanted. Unfortunately the low grade infection

recurred again. After two additional DAIR procedures the patient preferred an above-knee

amputation over another DAIR procedure, life-long antibiotics or a third 2-stage revision. At

present he is pain-free and ambulatory with an above knee prosthetic leg.

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Chapter twelve

Case 3

A 67 year old male had a TKR after years of indistinct progressive knee-pain. Peroperatively a

benign tumour with few giant cells was diagnosed as a coincidental finding. A few months later

a supra-patellar biopsy showed a mixed malignant appearance, including TGCT components.

Unexpectedly, lymphadenopathy on his groin, did not show malignant cells, but reactive

cells. The patient suffered of systemic symptoms: night sweats, weight loss and infection like

symptoms (not specified). Both for the lymphadenopathy and his painful right knee he received

radiotherapy (70 Gy on both locations, treatment for uncontrollable pain). Histopathologic

revision, by a tertiary specialized pathologist in a reference centre, showed a Dt-GCT. Aggressive

tumour progression, including bone-involvement provoked TKR failure (Figure 3, Figure 4a, Figure

4b). Within one year, several histologically proven Dt-GCT lung metastases were discovered.

Molecular research revealed a t(1;6)(p13;q27) translocation (Supplementary materials), this is

not the typical t(1;2)(p13,q33) translocation, however literature shows different variants on this

translocation. Final diagnosis through FISH technique confirmed Dt-GCT. Discomforting pulmonal

symptoms expressed multiple lung, pleural and costal metastases. Inside the thorax, numerous

suspected lymph nodes were seen. When he developed pulmonary symptoms; an investigational

TKI was started, which had an effect on his lung-metastases, but not on his irradiated painful

lymphademic leg (Figure 5a, Figure 5b). Complaints of tiredness, disguise, a very oedematous right

leg with a leaking protuberance and persisting anaemia provided discomfort. Attributed to the

TKI, pulmonary symptoms disappeared and his lung metastases stabilized. However, a hospital

admission due to pneumonia on both sides and pulmonary embolisms caused a repercussion. As

a last resort, the primary-tumour was resected by amputation, complicated with 4 Litres blood loss

and desaturation (until 90%), necessitating admission to the intensive care unit. Histopathology

confirmed Dt-GCT without malignant cells, however margins were not disease free. Residual and

recurrent disease was seen on MRI three months post-operatively and clinically observed. After

six months, a debulking procedure was performed on his amputated stump. The TKI did not show

effect on the metastases anymore and was discontinued after one year of compassionate use.

Currently, his phantom pain is acceptable.


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12

Figure 3 Metal artefact reducing

sequelae sagittal T2 weighted turbo

inversion recovery MR image of the right

knee of a 67 year old male patient, with a

TKR in situ. Extensive tumour progression

around TKR and bone invasion is shown.

Figure 4 a & b X-rays (anterior-posterior and sagittal) of failing total knee replacement, attributed to aggressive

TGCT progression including bone-involvement, after radiotherapy treatment.

a b

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Chapter twelve

Figure 5 a&b PET CT-scan showing extensive TGCT around the right knee-joint and multiple lung, pleural and

costal metastases. When pulmonary symptoms developed; an investigational tyrosine-kinase-inhibitor (TKI)

was started (a. prior to treatment, b. after treatment), which had an effect on his pulmonary-metastases, but

not on his irradiated painful lymphademic leg.


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Case 4

After years of indistinct knee-complaints, a biopsy proved Dt-GCT in a 17 year old male. Intra-

articular 90Yttrium was not effective. After a partial open synovectomy, Dt-GCT recurred. A two-

staged anterior and posterior synovectomy in two tempi (complicated by haemorrhage) was

performed at a tertiary oncology centre. During the following 13 years, the patient underwent a total

of seven surgeries in an effort to treat Dt-GCT, including a knee-arthrodesis using a compression

plate and screws (Figure 6). Osteosynthesis was removed several years later because of a low

grade osteomyelitis and persisting anaemia. Subsequently, a two-staged anterior and posterior

debulking synovectomy was performed (Figure 7 shows MRI prior to debulking). After another

debulking procedure, local tumour control did not seem feasible. An above knee amputation was

performed at the age of 30. Histopathological revision proved Dt-GCT, without malignant cells.

After several years of painless walking with an external prosthesis, pulmonary symptoms occurred.

Imatinib, an investigational TKI, chemotherapy and radiotherapy had no effect on pulmonary and

lymph node metastases. Despite all efforts, deterioration of the patient seemed irreversible. The

patient deceased at the age of 35 years.

Figure 6 Knee-arthrodesis after multiple

Dt-GCT surgeries in a 26 year old man,

using a compression plate and screws.

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Chapter twelve

Figure 7 Sagittal T1 weighted Spectral Presaturation with Inversion Recovery MR

image after intravenious contrast, of a 28 year old male patient revealing a large,

extra-articular TGCT tumour mass. Patients history describes multiple surgical

treatments, including removal of osteosynthesis material for a knee arthrodsesis.


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discussion

TGCT onset is typically slow and patients present with unspecified complaints1. Pain, swelling and

stiffness in the involved joint might be misinterpreted as osteoarthritis, rheumatoid arthritis, a

meniscal tear or other ligamentous injury2. Because of the rarity of the disease, definitive diagnosis

may take several years and patients present with extensive disease. Frequently, patients are referred

to a tertiary hospital, after several arthroscopic or open synovectomies and even radiotherapy

(case number 1)10, 11. Besides declined functional outcome and quality of life10, these patients are

at risk of repeated recurrences and extensive resistant disease7. Multiple surgeries increase the risk

of infection. Continued inflammation, joint usuration and bone involvement may lead to articular

destruction that might worsen (pre-existing) osteoarthritis2. A total joint replacement or even an

endoprosthetic-reconstruction may become inevitable8, 12. Occasionally, total joint arthroplasty

is the primary procedure performed in TGCT8. Only seldom, an above-knee amputation as a last

resort in treatment of TGCT is mentioned13-16.

Is an above knee amputation justified in an essentially benign, but locally aggressive disease? After

(major) complications, for example periprosthetic infections, in primary total knee arthroplasties,

above knee amputations are performed17, 18. Our amputation cases also attributed to severe

prosthetic infections (case 1 and 2). Radiotherapy, applied in case 1 (in a non-specialized hospital)

and 3 (in order to decrease severe pain-complaints), increases risk of prosthetic failure, infection

and wound healing. The overall prevalence of above-the-knee amputation after TKA is estimated

at 0.36%17. When severe pain, a swollen joint, limited range of motion and stiffness impair range

of motion: an above-knee amputation might increase patients mobility17, 19. Therefore, we feel

amputation is justified in extreme TGCT cases.

TGCT is a heterogeneous disease. Some cases are instantly diffusely spread intra- and extra-

articular or even show malignant characteristics. Metastases in histologically benign TGCT are

extremely rare, called an implantation phenomenon and conservatively treatment is suggested14.

Symptomatic free metastases in case 3 were conservatively treated. Physicians should be aware

of the potentially aggressive course of TGCT. Multiple mutilating surgeries decline functional

outcome and quality of life10. Expert centres need to cooperate on these rare cases to understand

the biology underlying these different clinical behaviours.

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Chapter twelve

West et al. discovered a central role for CSF1 in the pathogenesis of TGCT6. Multiple trials with

systemic therapies targeting CSF-1 receptor, show promising results as novel treatment method

for diffuse-TGCT7. Emactuzumab (RG7155) (a monoclonal antibody against CSF1R) showed an

objective response in 26 of 28 (86 %) TGCT patients20. Prolonged tumour regression is described

in patients, treated with tyrosine kinase inhibitor PLX339721. (Serious) adverse events in

emactuzumab and PLX3397 are investigated. Currently, two studies are recruiting patients with

recurrent or unresectable TGCT diffuse-type: MCS110 (a CSF1-directed monoclonal antibody,

NCT01643850) and FPA008 (an anti-CSF1R monoclonal antibody, NCT02471716). In the near

future, if these systemic treatments are approved, multiple surgeries and final limb amputation,

hopefully, will become obsolete.

To our knowledge, this is the first case-series focussing on limb-amputation after multiple

treatments of TGCT. In order to prevent extensive final treatments, like amputations, further

investigation of TGCT risk factors for recurrences is essential in proper primary-treatment planning.

In the orphan TGCT, knowledge of disease impact can be improved. Patients suffering extensive

disease including patients after multiple mutilating surgeries, might experience higher quality of

life once they feel in control of their own life again. Performing an above-knee amputation may

therefore be considered in extreme and extensive TGCT cases.

conclusion

Frequently, TGCT is successfully treated with radical surgical excision. In a substantial percentage

of cases, it presents as an aggressive and extensive disease that requires complex treatments,

and, in extreme cases, can even lead to limb-sacrificing surgery. Quick diagnosis and adequate

treatment of this rare condition are important factors for outcome. Therefore, it is essential that

these patients get referred to specialized centres at an early stage. We described four extensive

Dt-GCT cases, treated with an above-knee amputation as final treatment.


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references

1. de St. Aubain Somerhausen N, van de Rijn M. Tenosynovial giant cell tumour, localized type/diffuse type. In: Fletcher CD, Bridge JA,

Hogendoorn PC, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. 5. 4th ed. Lyon: IARC Press; 2013. p. 100-3.



3. Mankin H, Trahan C, Hornicek F. Pigmented villonodular synovitis of joints. Journal of surgical oncology. 2011;103(5):386-9.

4. van der Heijden L, Gibbons CL, Hassan AB, Kroep JR, Gelderblom H, van Rijswijk CS, et al. A multidisciplinary approach to giant cell

tumors of tendon sheath and synovium--a critical appraisal of literature and treatment proposal. J Surg Oncol. 2013;107(4):433-45.

5. Murphey MD, Rhee JH, Lewis RB, Fanburg-Smith JC, Flemming DJ, Walker EA. Pigmented villonodular synovitis: radiologic-

pathologic correlation. Radiographics. 2008;28(5):1493-518.

6. West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, et al. A landscape effect in tenosynovial giant-cell tumor

from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci U S A. 2006;103(3):690-5.

7. Stephan SR, Shallop B, Lackman R, Kim TW, Mulcahey MK. Pigmented Villonodular Synovitis: A Comprehensive Review and

Proposed Treatment Algorithm. JBJS Rev. 2016;4(7).


orthopaedica. 2016:1-7.

9. van der Heijden L, Piner SR, van de Sande MA. Pigmented villonodular synovitis: a crowdsourcing study of two hundred and

seventy two patients. Int Orthop. 2016;40(12):2459-68.

10. van der Heijden L, Mastboom MJ, Dijkstra PD, van de Sande MA. Functional outcome and quality of life after the surgical treatment

for diffuse-type giant-cell tumour around the knee: a retrospective analysis of 30 patients. Bone Joint J. 2014;96-B(8):1111-8.

11. Flandry F, Hughston JC, McCann SB, Kurtz DM. Diagnostic features of diffuse pigmented villonodular synovitis of the knee.

Clinical orthopaedics and related research. 1994(298):212-20.

12. Gonzalez Della Valle A, Piccaluga F, Potter HG, Salvati EA, Pusso R. Pigmented villonodular synovitis of the hip: 2- to 23-year

followup study. Clin Orthop Relat Res. 2001(388):187-99.

13. Layfield LJ, Meloni-Ehrig A, Liu K, Shepard R, Harrelson JM. Malignant giant cell tumor of synovium (malignant pigmented

villonodular synovitis). Archives of pathology & laboratory medicine. 2000;124(11):1636-41.

14. Asano N, Yoshida A, Kobayashi E, Yamaguchi T, Kawai A. Multiple metastases from histologically benign intraarticular diffuse-

type tenosynovial giant cell tumor: a case report. Human pathology. 2014;45(11):2355-8.

15. Hamlin BR, Duffy GP, Trousdale RT, Morrey BF. Total knee arthroplasty in patients who have pigmented villonodular synovitis.

The Journal of bone and joint surgery American volume. 1998;80(1):76-82.



17. Sierra RJ, Trousdale RT, Pagnano MW. Above-the-knee amputation after a total knee replacement: prevalence, etiology, and

functional outcome. The Journal of bone and joint surgery American volume. 2003;85-a(6):1000-4.

18. Khanna V, Tushinski DM, Soever LJ, Vincent AD, Backstein DJ. Above knee amputation following total knee arthroplasty: when

enough is enough. The Journal of arthroplasty. 2015;30(4):658-62.

19. Fedorka CJ, Chen AF, McGarry WM, Parvizi J, Klatt BA. Functional ability after above-the-knee amputation for infected total

knee arthroplasty. Clinical orthopaedics and related research. 2011;469(4):1024-32.

20. Cassier PA, Italiano A, Gomez-Roca CA et al., CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell

tumours of the soft tissue: A doseescalation and dose-expansion phase 1 study, The Lancet Oncology, vol. 16, no. 8, pp. 949–956, 2015.

21. Tap WD, Wainberg ZA, Anthony SP et al., “Structureguided blockade of CSF1R kinase in tenosynovial giant-cell tumor,” New

England Journal of Medicine, vol. 373, no. 5, pp. 428–437, 2015.

su

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summaryof this thesis

278

Chapter thirteen

summary of thesis

Both localized- and diffuse-type tenosynovial giant cell tumours (TGCT) are defined a benign

disease as metastases or lethal outcome very rarely occur. Diffuse-type TGCTs are regarded

more challenging to treat because they have an infiltrating growth pattern and lack anatomical

boundaries which make complete resection difficult and at times technically impossible or

undesirable with joint function preservation and health-related quality of life in mind. Within

this present era of systemic targeted and multimodality therapies (available in trial settings),

standalone surgical resection cannot be regarded as the gold standard anymore for all cases.

This thesis aims to unravel the heterogeneity of TGCT, to improve oncologic results and maintain

joint functionality and health-related quality of life, by addressing several disease aspects.

Patient selection for different treatment options is improved by translational research, risk factor

identification, treatment outcome evaluation and disease severity stratification.

Up to date incidence calculations are necessary for diagnostic purposes. Therefore, chapter 2

determined worldwide incidence rates in TGCT affecting digits, TGCT localized-extremity and

TGCT diffuse-type. Previous incidence rate calculations originated from 1980, in which a US county

study calculated an incidence rate of 9 and 2 per million person-year in localized- (including digits)

and diffuse-TGCT, respectively (Myers 1980). By use of PALGA, the non-profit nationwide network

and registry of histo- and cytopathology in The Netherlands, a search was performed for TGCT in

a 5-year time frame. Subsequently these data were clinically verified in the corresponding Dutch

hospitals. Dutch TGCT incidence calculations were converted to world population incidence rates.

Finally, incidence rates of TGCT affecting digits was 29, localized-type extremity TGCT 10 and

diffuse-type TGCT 4 per million person-years. All three groups showed a female predilection and

highest number of new cases in age-category 40 to 59 years. The knee was most often affected:

localized-extremity (46%) and diffuse-type (64%), mostly treated with open-resection: localized

(65%) and diffuse (49%). Reoperation rate due to local recurrence for localized-extremity was 9%,

diffuse-TGCT 23%. Compared to the initial US-county study, our study showed a 5-fold higher

incidence rate in localized-type (combining localized-digits and localized-extremity), and a more

than 2.6 fold higher incidence rate in diffuse-type. This difference could be attributed to our

nationwide coverage and because of increased awareness about the disease.


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The controversy that localized- and diffuse-type TGCT are clinically and radiologically two different

types, while histopathologically they seem indistinguishable is evaluated in chapter 3. Abundant

expression of Colony Stimulating Factor1 (CSF1), due to genomic rearrangements, is believed to

be the driver mechanism in tumour formation. This study aimed to correlate CSF1-expression

and CSF1-rearrangement with the biological behaviour of different TGCT-types and with clinical

outcome (recurrence). Along a continuum of extremes, therapy naïve knee TGCT patients with

>3-year follow-up, mean age 43 (range 6-71) years, 56% female were selected. Nine localized- (two

recurrences), 16 diffuse-type (nine recurrences) and four synovitis as control were included. The

use of CSF1 split-apart FISH, consecutive to mRNA ISH, showed to be an auxiliary diagnostic tool,

with 76% of TGCT harbouring CSF1-gene rearrangement. A clear association was not revealed

between CSF1 over-expression or CSF1 rearrangement and the biological behaviour of different

TGCT-characteristics (e.g. localized-/diffuse-type and clinical outcome (recurrence)) of the knee.

Since localized- and diffuse-TGCT differ clinically, chapter 4 established a severity classification

to stratify different disease severity stages. This classification may aid to identify eligible patients

for systemic targeted therapy or trials for novel agents. Parameters were defined by field-experts

to assess disease extension on MR images. Type of TGCT, articular involvement, involvement of

muscular/tendinous tissue and ligaments showed good inter- and intra-rater agreement (Kappa

≥0.66), had adequate number of presence (minimum of 20%) and yielded positive association

on first recurrence. Ranging from highest to lowest hazard ratios these four MR parameters

constructed the TGCT severity classification for all large joints, including four distinct severity-

stages. Recurrence free survival at 4 years (log rank p<0.0001) was 94% in mild localized, 88% in

severe localized, 59% in moderate diffuse and 36% in severe diffuse. The TGCT severity classification

informs physicians and patients on disease extent and risk for first local recurrence after surgical

treatment.

As the clinical behaviour of TGCT is very heterogeneous and probably multifactorial, chapter 5

evaluated the unexplored influence of female sex hormones on symptoms in TGCT. Female sex

hormones (oestrogen and progesterone) elevate during pregnancy. Since an increase in TGCT-

related symptoms during pregnancy is observed in the outpatient clinic and on online TGCT

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Chapter thirteen

patient fora, we hypothesized that these increased symptoms were influenced by female sex

hormones. Fifty-six percent of pregnant patients reported an increase in TGCT-related symptoms,

predominantly swelling of the affected joint. Influences of sex specific hormones and female

fertile life phase specific hormones were determined by comparing recurrence free survival

rates between the sexes and pre- versus post-menopausal women. No differences were found

in recurrence free survival rates, between both sexes, (localized- (p=0.206 ≤50 years, p=0.935

>50 years); diffuse-type (p=0.664 ≤50 years, p=0.140 >50 years)), neither in pre- versus post-

menopausal women (localized- (p=0.106); diffuse-type (p=0.666)). This makes a causal relation

with female sex hormones unlikely. Finally, presence of female sex hormonal receptor-status in

available tumour tissue was assessed. In all examined localized- and diffuse-TGCT tissue-samples,

oestrogen or progesterone hormone-receptor staining was negative and could therewith not be

linked to the increased TGCT-related symptoms.

Many case-series in adults are described, whereas only 76 pediatric patients with TGCT were

reported, according to our systematic review, presented in chapter 6. This study compared TGCT

in children with TGCT in adults, calculated incidence rate and evaluated clinical behavior of TGCT

in children. The standardized pediatric TGCT incidence rate of large joints was 2.42 and 1.09 per

million person-years in localized and diffuse types, respectively. In 57 children diagnosed and

treated between 1995 and 2015, in one of the four tertiary sarcoma centers in The Netherlands,

symptoms were swelling, pain, and limited range of motion with a median time before diagnosis

of 12 (range 1-72) months. With the numbers available, differences in presentation between

children and adults were not observed in terms of sex, symptoms before diagnosis, first treatment,

recurrent disease, follow-up status, or median time to follow-up. The 2.5-year recurrence-free TGCT

survival rate after open resection was similar between children and adults: 85% (95%CI 67%-100%)

versus 89% (95%CI 83%-96%) in localized, respectively (p=0.527) and 53% (95%CI 35%-79%)

versus 56% (95%CI 49%-64%) in diffuse type, respectively (p=0.691). Although the incidence of

pediatric TGCT is low, it should be considered in the differential diagnosis in children with chronic

mono-articular joint effusions. Recurrent disease after surgical treatment of this orphan disease

was comparable between children and adults.


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In the literature, chapter 7 and chapter 8 presented the largest series of both localized- and

diffuse-type TGCT. Two-thousand one-hundred and sixty-nine (941 localized-, 1192 diffuse-, 36

unknown-type) histologically proven TGCT cases of large joints were included, treated between

1990-2017 in one of 31 collaborating sarcoma centers globally.

In localized-TGCT (chapter 7), 62% was female with median age at first treatment of 39 years and

median follow-up of 37 months. 67% affected the knee and primary treatment at tertiary center

was one-staged open resection in 71%. Total number of recurrent disease was 13% with local

recurrence free survival at 3, 5 and 10 years of 88%, 83% and 79% respectively. The largest risk

factor for recurrent disease was prior recurrence (p<0.001). Complications were noted in 4% after

surgical treatment of localized-TGCT. Initial symptoms of pain and swelling improved after surgical

treatment(s) in 71% and 85%. Only including therapy naïve cases, tumour size ≥5 cm versus

<5cm HR 2.50(95%CI 1.32-4.74;p=0.005) and initial treatment with arthroscopy versus open HR

2.18(95%CI0.98-4.84;p=0.056) yielded positive association with local recurrence in both univariate

and multivariate analyses. Relatively low complication rates and good functional outcome warrant

an open approach with complete resection in localized-TGCT, to reduce recurrence rates in high

risk patients.

In diffuse-TGCT (chapter 8), 58% was female, median age 35 years and median follow-up 54

months. 64% affected the knee and in 53% primary treatment was one-staged open synovectomy.

45% had first local recurrence, accompanied with local recurrence free survival at 3, 5 and 10 years

of 62%, 55% and 40%, respectively. Largest risk factor for recurrent disease was prior recurrence

(HR 3.5 95%CI 2.8-4.4, p<0.001) with a 5 years RFS in therapy naïve patients compared with

patients treated elsewhere of 64% and 25%, respectively. Complications were noted in 12%.

Initial symptoms of pain and swelling improved after surgical treatment(s) in 59% and 72% of

patients respectively. In a subgroup analyses including therapy naïve cases affecting the knee,

neither sex (male;female), age (≤35years;>35years), bone-involvement (present;absent), surgical

technique (open;arthroscopic) nor tumour size (<5cm;≥5cm) yielded an association with first local

recurrence. Since complete resection of diffuse-TGCT could be regarded as nearly impossible and

recurrence rates are unacceptably high after both arthroscopy and open synovectomy in the knee,

even in specialized centres, standalone surgical resection cannot be regarded the gold standard

anymore in the era of multimodality therapies.

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Chapter 9 described long term effects of imatinib mesylate, a non-selective CSF1 inhibitor, in

TGCT. Sixty-two patients from 12 institutions across Europe, Australia and the United States used

imatinib as treatment. Thirty-nine patients were female (63%), median age at treatment start was

45 years, with a median time from diagnose to treatment of 3.5 years. Median follow-up after

treatment start was 52 months. Four patients with metastatic TGCT progressed rapidly on imatinib

mesylate and were excluded for further analyses. Seventeen (29%) of 58 evaluable patients

achieved complete or partial response. One- and five-year progression-free survival rates were

71% and 48%, respectively. Thirty-eight (66%) patients discontinued imatinib after a median of 7

months. Reported adverse events in 45 (78%) patients were mostly grade 1-2 (89%) (e.g. edema

(48%) and fatigue (50%)). Five patients experienced grade 3-4 toxicities, including neutropenia,

acute hepatitis, facial edema, skin toxicity and fatigue. This study confirmed the known efficacy

of imatinib in TGCT. In responding cases, prolonged activity of imatinib on TGCT symptoms

was confirmed, even after discontinuation, but with high rates of treatment interruption and

additional treatments. Limitations of this study are related to the retrospective study design,

the lack of a control group and the absence of patient reported outcome measures. To evaluate

patients reported outcome measures, chapter 10 focused on joint function and health-related

quality of life outcome after surgical treatment in a prospective cohort study. Patient-reported

outcome measures (Short Form (SF)-36, Visual Analogue Scale (VAS) and Western Ontario and

McMaster Universities Osteoarthritis Index (WOMAC)) were assessed in a homogeneous group

of 206 consecutive patients with localized- (N=108) and diffuse-type (N=98) TGCT of large joints,

initially treated with (arthroscopic/open) synovectomy at either Leiden University Medical

Center or Radboud University Medical Center. In particular, the physical component of SF-36

subscales showed significant and clinically relevant deteriorated scores preoperative- and direct

postoperative compared with general population means, in both localized- and diffuse-TGCT. Six

months after surgery, SF-36 scores improved to general population means and continued fairly

stable the following years. Median pain (VAS) scores, for both-subtypes, showed no clinically relevant

difference pre- or postoperatively. Pain experience differed tremendously between patients and

over time. Mean function (WOMAC) scores, for both TGCT subtypes, showed no clinically relevant

differences (effect size < MCID 20) pre- versus postoperatively. However, in diffuse-type patients

WOMAC pain and physical function scores showed a trend toward improved preoperative versus

postoperative scores. To conclude, patients report a significant better health-related quality


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of life after surgery in TGCT whereas joint function showed a trend towards improvement. To

evaluate patient reported outcomes in an even larger group of patients, chapter 11 conducted a

crowdsourcing study in the largest TGCT patient support group. To evaluate the impact of TGCT

on daily living; physical function, daily activities, societal participation (work, sports and hobbies)

and overall health-related quality of life was assessed. Secondary aim was to define risk factors

for deteriorated outcome in TGCT with the use of validated questionnaires (VAS for worst pain

and stiffness, Patient Reported Outcomes Measurement Information System-physical functioning

(PROMIS-PF), SF-12 and EuroQoL (EQ-5D-5L)). In a timeframe of six months, TGCT patients were

invited to complete the online questionnaire. To confirm disease presence and TGCT-type, patients

were requested to share histological- or radiological-proof of TGCT. Three-hundred thirty-seven

questionnaires (32% with disease confirmation), originating from 30 countries, were completed.

Median age at diagnosis was 33 (IQR 25-42) years, majority was female (80%), diffuse-TGCT (70%)

and affected lower extremities: knee (71%) and hip (10%). In 299 lower extremity TGCT-patients,

recurrence-rate was 36% and 70% in localized- and diffuse-type, respectively. Due to TGCT, 13%

of localized- and 11% of diffuse-type was unable to (fully) perform their employment and 58%

of localized- and 64% of diffuse-type was unable to practice sport-activities. For both types, pain

and swelling decreased after treatment, but stiffness worsened and range of motion decreased.

This could be attributed to (multiple) surgical treatments, inducing scar tissue, cartilage wear

and adhesions. Compared with general United States population, all patients showed declined,

clinically relevant, PROMIS-PF scores, SF-12 physical and mental scores and EQ-5D-5L utility-score.

When comparing localized- and diffuse-TGCT, diffuse-type scored almost 0.5 standard-deviation

lower for PROMIS-PF (p<0.001) and 5% lower for EQ-5D-5L (p=0.03). In localized-TGCT, recurrent

disease and ≥2 surgeries negatively influenced scores of VAS-pain/stiffness, SF-12 physical and EQ-

5D-5L (p<0.05). In diffuse-type, recurrence resulted in lower score for VAS-pain/stiffness, PROMIS-

PF, SF-12 mental and EQ-5D-5L (p<0.05). In both types, patients with treatment ≤1 year ago scored

significantly lower on SF-12 physical. This study demonstrated that TGCT has major impact on

daily living in a relatively young and working population. Physicians and other relevant health

care providers (e.g. physiotherapists) should be aware that TGCT patients frequently continue to

experience declined health-related quality of life and physical function and often remain limited

in daily activities, employment and sports, even after treatment(s).

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Extreme final treatment measures in TGCT, an above knee amputation, are presented in chapter

12. High recurrence rates are known in diffuse-TGCT (up to 92%), necessitating reoperations and

adjuvant treatments. Once all treatments fail or if severe complications occur, limb amputation

may become unavoidable. Four cases treated with this last resort treatment for TGCT, an above-

knee amputation, were described.

Conclusions, clinical implications and future perspectives for the subject of this thesis are discussed

in chapter 14.


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general discussion

In the 2013 WHO classification of tumours of soft tissue and bone, giant cell tumour of the tendon

sheath and pigmented villonodular synovitis (PVNS) were unified in one overarching name:

tenosynovial giant cell tumours (TGCT)1, 2. To date, among most treating physicians, the disease

still remains best known with the term PVNS3. With this thesis, we want to create disease awareness

and update knowledge on disease and treatment outcome.

TGCT is a rare heterogeneous disease (chapter 2) with a wide clinical spectrum; patients of all ages

are affected (chapter 5 and 6), including different joints (both small and large), various disease

stages and severities. This heterogeneity challenges research initiatives, as current literature mainly

consists of relatively small single centre observational case-series that often compare apples to

oranges. Frequently, series have a retrospective design and level of evidence is not exceeding level

III-IV. To achieve solutions on unmet medical needs, we need to set up research projects that reach

higher levels of evidence through thorough (inter)national, multicentre collaborative studies.

1. Translational research

The translocation (1;2)(p13;q35) that is responsible for overexpression of Colony Stimulating Factor

1 (CSF1), is thought to be the driver mechanism of this disease4, 5. It remains unclear when and

why this translocation forms, but it remains a ‘local problem’ as TGCT is a mono-articular disease.

An unravelled clinical question is how to differentiate the biological behaviour of different TGCT-

types with clinical outcome (recurrence). All TGCT cases show CSF1 over-expression. By the use of

correlative microscopy for CSF1 mRNA ISH and consecutive CSF1 split-apart FISH, we were able to

detect CSF1-gene rearrangement in 76% of the TGCT cases; 77% for localized-TGCT and 75% for

diffuse-TGCT. The relatively high percentage of rearrangement in our study could be attributed to

our scoring on preselected areas, based on high CSF1 expression. In addition, our DNA FISH analysis,

using bacterial artificial chromosome (BAC) clones (RP11-354C7 and RP11-96F24) bracketing

CSF1 locus, identified not only a translocation, but also an inversion for CSF1 rearrangements. In

diagnosing TGCT, CSF1 mRNA-ISH in combination with CSF1 split-apart FISH; using digital correlative

microscopy, is an auxiliary diagnostic tool to identify rarely occurring neoplastic cells. Although this

helps the diagnostic process, in chapter 3 we were unable to use this technique and differentiate for

biological behaviour of TGCT by evaluating CSF1 over-expression or rearrangement.


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2. Individually tailored treatment

Physical joint examination is generally nonspecific in the clinical diagnosis of TGCT. A specialized

musculoskeletal radiologist can however diagnose TGCT on magnetic resonance (MR) imaging,

which is the most distinctive imaging technique6-10. MR imaging can also be a differentiating tool

to determine tumour severity staging and for evaluation of disease extent during follow-up. The

TGCT severity classification in chapter 4 defines TGCT extension on MR imaging to classify disease

severity. This classification, including four distinct severity-stages, could attribute to a treatment

strategy flowchart and improve the homogeneity in clinical studies. Definitive diagnosis however

is established by histopathology, either by biopsy or surgical resection.

The fundamental question whether curation is necessary in a locally aggressive disease often

arises in literature. Debilitating symptoms and (progressive) joint destruction commonly

result in treatment of the diseased tissue. At present, the choice of treatment is established by

preference of the patient, treating physician and might differ per centre. Most common performed

treatment is surgical excision, aiming for local tumour control. Localized-TGCT presents as a well

circumscribed lesion and recurrence rates after arthroscopic and open synovectomy are reported

similar (6% after arthroscopic and 4% after open synovectomy)11. Surgical treatment for the

locally aggressive diffuse-TGCT is more challenging, as pathologic tissue can be widely spread

and technically difficult to reach. In extensive disease (chapter 4, severe diffuse stage), irradical

resection could be preferred with joint preservation in mind. However, higher rates of recurrences

are described after macroscopically incomplete resections12-15. As primary treatment for diffuse-

TGCT, either an arthroscopic- or (one- or two staged) open synovectomy or a combination of these

two treatments is performed. Physicians in favour of arthroscopic resection claim fast recovery,

a lower complication rate and less joint morbidity13, 16-22. However, frequently at the cost of

inadequate excision, high recurrence rates (on average 40% in diffuse-TGCT) and a theoretical risk

of joint seeding and portal contamination11, 23. A complete synovectomy is generally impossible

with traditional arthroscopy, therefore Blanco et al. and Mollon et al. used multiple portals in

arthroscopic synovectomy24, 25. Chin et al. stated that knee arthroscopy is an inferior treatment

for extra-articular TGCT26. Nowadays, open synovectomy, either one- or two-staged, is the

preferred surgical therapy in most centres, because of clear tumour visibility and lower short term

recurrence rates (on average 14% in diffuse-TGCT)11, 27, 28. The disadvantage of a one- or two-staged

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open resection, could be deteriorated joint function accompanied with decreased health-related

quality of life (chapter 9)29. A combined anterior arthroscopic- and posterior open synovectomy

in the knee is only incidentally reported. Mollon et al. described the combined approach of an

anterior arthroscopy and posterior open synovectomy (N=15 patients), with low recurrence

rates25. Colman et al. retrospectively subdivided 48 diffuse-TGCT patients in three groups; either

treatment with an arthroscopy, the combined approach or an open approach. They concluded

that the combined approach is a feasible option because of relatively low short term recurrence

rates (9%)30. Chapter 7 revealed that the longer the follow-up, the higher the recurrence rates.

Localized-TGCT had a recurrence rate of 21% and diffuse-TGCT 69% after initial surgical resection

at a tertiary oncology centre with a follow-up of more than 10 years. The suspicion arouses that

most patients will develop a recurrence when you wait long enough. The main question remains:

is the recurrent disease accompanied by debilitating symptoms or joint destruction?

In general, all surgical treatments harbour the risk of complications. Literature frequently lacks

descriptions of complications. Chapter 7 reports a complication rate of 4% in localized-TGCT and

12% in diffuse-TGCT after initial surgical treatment at a tertiary centre. Most common complication

in diffuse-TGCT was joint stiffness, which might be difficult to prevent in surgical treatment of

extensive disease.

In extensive diffuse disease, radical excision is next to impossible as residual tumour cells (micro- R1

or macroscopically R2) may persist. In diffuse-TGCT, joint destruction and secondary osteoarthritis

is frequently present. When chronic symptoms persist, joint arthroplasty might become inevitable,

especially in large joints with tight capsules including a higher risk of bone involvement, such as

the hip and ankle29, 31, 32.

A combination of surgery and external beam radiation is considered in extensive or recurrent

diffuse-TGCT. Radiotherapy may kill residual tumour cells, but possibly at the cost of increased

(delayed) complications, especially in re-operation, and impaired functional outcome15, 33-35. Blanco

et al. reported that partial arthroscopic synovectomy of the knee combined with external beam

radiation might reduce the risk of recurrence (N=22 patients)24. A meta-analysis suggested that

open synovectomy (N=19 studies) or synovectomy combined with perioperative radiotherapy

(N=11 studies) is associated with a reduced rate of recurrence34. Mollon et al. reserved additional


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external beam radiation for patients at high risk for local recurrence, if they had the following

characteristics: multiple recurrent intra-articular disease, extra-articular extension, or gross

residual disease remaining following surgery25. Currently, sufficient data including adequate

patient numbers is lacking to support the additional value of external beam radiation in primary

cases and should only be performed in specific extensive or recurrent diffuse-TGCT cases.

Additional reported treatment modalities include radiation synovectomy with 90yttrium36 and

cryosurgery37, 38, for which the therapeutic value is inconclusive and their long-term side effects

and complications are unknown. Bickels et al. treated seven patients with diffuse-TGCT of the

ankle with subtotal synovectomy and intra-articular 90yttrium and warned not to use 90yttrium

as additional treatment because of unacceptable high rate of serious complications39. Gortzak et

al. reported no significant differences in residual disease, complication rate and overall physical

and mental health scores between patients surgically treated for TGCT of the knee with (N=34) or

without (N=22) adjuvant 90Yttrium, after a mean follow-up of 7.3 years36. Chin et al. subdivided

patients, after surgical resection without disease eradication, into three groups: group I

combined arthroscopic and open synovectomy (five patients), group II combined synovectomy in

combination with intra-articular radiation synovectomy (dysprosium-165) (30 patients), and group

III combined resection and three months postoperatively external beam radiation (five patients).

They concluded that group I and Group II showed similar increases in postoperative flexion

compared with group III15. Verspoor et al. evaluated 12 patients treated with surgical synovectomy

and additional cryosurgery. They did not find better results compared to surgical resection alone37.

Diffuse-TGCT grows locally aggressive. Therefore, systemic therapy, with possible (severe) side

effects, seems justified in this benign but debilitating disease. Colony Stimulating Factor1 (CSF1),

due to genomic rearrangements, is believed to be the driver mechanism in tumour formation. By

a paracrine loop, the CSF1 excreting tumour cells, attract non-neoplastic cells, carrying the CSF1

receptor. Interruption of this pathway is the aim of systemic targeted therapies. Targeted therapy

might be used as treatment independently or to primarily down-stage the disease and facilitate

consecutive surgical resection. Non-selective CSF1 inhibitor therapies with nilotinib40 or imatinib

(chapter 8) and newer, more potent selective CSF1 inhibitors such as pexidartinib41, emactuzumab42,

cabiralizumab43; or a monoclonal antibody such as MSC110 (clinicaltrial.gov) seem promising.

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Results are usually tumour-centric presented, using Response Evaluation Criteria in Solid Tumors

(RECIST); complete response, partial response, stable disease and progressive disease; and patient

centric, using symptom improvement evaluation. In a randomized, placebo-controlled phase 3

study, pexidartinib showed an improved overall response rate (complete response and partial

response merged) of 39% in the pexidartinib-group (N=61) and 0% of placebo-group (N=59), after

median six months follow-up. PROMIS physical function, worst stiffness and pain response was

significantly better in patients treated with pexidartinib41. Emactuzumab (N=29) had an overall

response rate of 86% and a rate of disease control of 96%, including a significant functional and

symptomatic improvement (median follow up 12 months)42. Preliminary results of cabiralizumab

showed partial response in 5 out of 11 patients and positive functional status improvements by

Ogilvie-Harris score (from 2 to 7)43. Ogilvie-Harris score combines pain, synovitis, range of motion

and functional capacity on a scale of 0 to 12.

Complete response was reported in a total of four patients; two patients treated with

emactuzumab42 and two patients treated with imatinib, presented in chapter 8.

Reported mild side effects include edema, change of hair colour, fatigue, nausea and skin rash/

dermatitis, but also moderate to severe side effects such as neutropenia, acute hepatitis, facial

edema, skin toxicity and fatigue. Despite these side effects, in selected patients with extensive and

recurrent diffuse-TGCT, CSF1 inhibitors might offer a solution. Treatment optimization is yet to be

established; optimal agent, therapy duration, timing of surgery, toxicity profile and mechanism of

resistance.

A challenging rare subgroup of soft tissue sarcoma patients, comprises multifocal, malignant or

metastatic disease resembling TGCT (four patients with metastatic TGCT in chapter 8 and two

patients in chapter 11). These patients are incidentally reported in case-series44. The largest series

of Li et al. included seven patients with malignant TGCT and concluded that these tumours should

be regarded as a distinct sarcoma with considerable morphologic variability, metastatic propensity,

and lethality45. As specialized centres see these patients extremely rare, upcoming research should

reveal whether TGCT is capable of malignant transformation or whether this malignant tumour

should be regarded a different (malignant) entity.


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To summarize, several treatment modalities in the heterogeneous disease TGCT are available.

Current literature fails to specify patient characteristics per treatment modality and lacks

randomized controlled trials, impeding definitive treatment of choice for each individual, based

on efficacy and safety. A solution for the difficulty of performing a randomized controlled trial

might be the so called stepped wedge cluster design. This is a special form of a randomised study

in which an intervention at group level is implemented in stages46. To contribute to personalized

treatment, careful evaluation of health-related quality of life and functional outcome (chapter 9

and 10), not just local recurrence and complications, should be included in patient follow-up. In

addition, large scaled studies based on individual participant data meta-analysis provide a higher

form of evidence in comparison with small heterogeneous case series. Advantages include that

missing data can be accounted for at the individual level, subgroup analyses can be performed

(e.g. per affected joint) and up to date disease status or follow-up information can be updated

continuously (chapter 7)47.

3. Centralized treatment in a multidisciplinary team

TGCT onset is typically slow and patients present with unspecified symptoms1, 2, 48, 49. Pain, swelling,

and stiffness of the involved joint might be misinterpreted as osteoarthritis, rheumatoid arthritis, a

meniscal tear, or other ligamentous injury50. Because of the rarity of the disease, definitive diagnosis

may take several years and patients present with extensive disease11, 51, 52. After several (arthroscopic

or open) synovectomies and even radiotherapy, patients are still referred to a tertiary hospital.

Besides declined functional outcome and health-related quality of life, these patients are at risk

of repeated recurrences, therapy resistant disease and higher risk of complications29. Continued

inflammation, joint usuration and bone involvement may lead to articular destruction that might

worsen (pre-existing) osteoarthritis50. By creating more public awareness, involving relevant

dedicated health care providers (e.g. rheumatologists, general practitioners, physiotherapists),

delay of diagnosis should be reduced by referring patients to specialized centres at an early

stage to provide optimal treatment(s)53. Specialized centres treat multiple patients with TGCT

and this rare disease is considered daily practice. Therefore, all members of the multidisciplinary

team are highly trained to recognize disease specifics. Members of the multidisciplinary TGCT

team include dedicated physicians with experience in musculoskeletal oncology in the field of

pathology, radiology, orthopaedic oncology, arthroscopic orthopaedics, radiotherapy, medical

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oncology and if necessary paediatric orthopaedics. To prevent end stage treatment options, such

as limb amputation (chapter 11), centralization of treatment should become state of the art.

Two examples of advantages of centralization of treatment are provided by the tertiary oncology

centre in Leiden (LUMC). Every half year a patient centred newsletter is send to all patients with

TGCT. This newsletter includes information on recent literature and (new) studies at patient level.

In addition, the TGCT-team of the LUMC is active on Facebook, with their own up to date Facebook

page (‘TGCT study’) and within the closed Facebook-group ‘PVNS is pants’ (chapter 10).

4. Patient-centred outcome measures

Outcome of TGCT treatments should be measured on how the patient is feeling. The mantra

for patient-centred treatment is: don’t make the treatment worse than the problem. Perhaps a

debilitating operation costs more than the disease itself in the view of health-related quality of life and

joint function preservation. Taking the factor time into account is necessary, as short term satisfying

results could emerge into deteriorated outcome in the long run. Defining specific treatment options

for each individual patient is of utmost importance. Would this individual patient benefit more from

conservative treatment or side effects of targeted therapy? Mild side effects might be considered

acceptable, however moderate to severe side effects seem less justifiable in a non-lethal disease.

Assessment of health-related quality of life and functional outcome in TGCT is necessary. However,

specific patient reported outcome instruments have yet to be defined. A few studies, including

chapter 9 and 10, have reported disease outcome from a patient perspective15, 25, 29, 36, 48, 54, 55. Used

validated questionnaires included worst pain and worst stiffness numeric rating scale (NRS), short

form (SF) health survey-12 and SF-36, Euroqol 5 (EQ5D5L), knee-injury osteoarthritis outcome

score (KOOS), hip disability osteoarthritis outcome score (HOOS), Toronto extremity salvage score

(TESS), musculoskeletal tumour society (MSTS) score, patient reported outcomes measurement

information system physical function (PROMIS-PF) and Western Ontario and McMaster Universities

Osteoarthritis Index (WOMAC). None of these patient reported outcome instruments are specifically

designed for rarely lethal, but morbid musculoskeletal tumours. Gelhorn et al. performed research

interviews regarding symptom experience to test the relevance and content validity of several

existing patient reported outcome instruments. They recommended PROMIS-PF as most suitable

questionnaire48. PROMIS-PF is subdivided in an upper- (11 questions) and lower-extremity part (13


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questions). Since TGCT affects all joints, measurements eligible for all these locations would be the

aim. In addition, general health-related quality of life measures are important to compare TGCT

with other musculoskeletal disorders.

A major disadvantage of standardized questionnaires is that they include questions not applicable

for each individual participant. Therefore, the item response theory (IRT) and Computer Adaptive

Testing (CAT) are developed. IRT examines the response characteristics of individual items and

the relationship between responses to individual items and the responses to each other item

in a domain. By using IRT, CAT is a method that selects subsequent questions (from the item

bank) based on the responses until predetermined termination criteria are met. Hereby only

relevant questions are asked and the amount of questions is greatly reduced. This ensures a

higher amount of patients willing to complete the questionnaire56. Relevant questions could be

extracted from the PROMIS databank, including over 300 measures of physical, mental, and social

health for use with the general population and with individuals living with chronic conditions

(http://www.healthmeasures.net). For future self-reported outcome evaluations in TGCT, we

would propose the CAT method by use of the PROMIS item bank.

Besides well-defined subjective outcome measures, objective outcome measures also need to be

determined to structure clinical evaluation. The timed up and go test provides information on

physical strength by measuring the time (seconds) to rise from and return to a chair with three

meters walking in between57. Another functional measure is the six-minute walk test, not just

determining joint range of motion, but looking at performance of the individual58.

5. Limitations

This thesis consists of multiple cohort studies. At times, patients are present in several cohorts.

Patients treated in the RadboudUMC or LUMC, were also present in the PALGA search to calculate

the incidence (chapter 2). In the evaluation of impact on daily living (chapter 11), a Facebook

cohort is used in which Dutch patients were present, which were also registered with the PALGA

search. This overlap of patients in the cohort studies could have influenced the results. However,

since each study had a unique research question to evaluate different aspects of the disease, this

influence is considered minimal.

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To conclude, TGCT is a chronic debilitating illness with large impact on daily living. It is a challenge

for physicians to provide optimal personalized treatment, since TGCT patients present as a

heterogeneous group, trials with targeted therapies are ongoing and a standardized treatment

algorithm is lacking. Based on our experience, literature and the TGCT severity classification

on MR imaging* (chapter 4), we propose a treatment algorithm for TGCT of all large joints as

a foundation to build upon and to evolve (figure 1 and figure 2). In addition to the physical and

financial burden for the patient, TGCT also involves a high healthcare burden with rising costs after

diagnosis59. Current developments are promising: increasing disease awareness, centralization

of care, several targeted therapy trials, evaluation of personalized follow-up questionnaires and

ongoing prospective international collaboration studies. These initiatives should be expanded to

achieve new insights in TGCT.

*The TGCT severity classification on MR imaging contains four distinct severity stages:

1. Mild localized contains localized-type, either intra- or extra-articular involvement


2. Severe localized includes localized-type, either intra- or extra-articular lesions and

either or both involvement of muscular/tendinous tissue/ligaments.

3. Moderate diffuse comprises diffuse-type with intra- and/or extra-articular disease


4. Severe diffuse is diffuse-type including intra- and extra-articular involvement and

involvement of at least one of the three structures (muscular/tendinous tissue/ligaments)


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Future perspectives

1. Translational research

The driver mechanism in TGCT tumour formation seems to be over-expression of CSF1. Only

a minority (2-16%) of cells in the tumorous tissue harbour the CSF1 rearrangement4, 5. Despite

the few tumour cells, they disrupt the entire surrounding area in different degrees of extent. We

expect the neoplastic cell to be a synovial like mononuclear cell, as was proposed by West et

al.4 They reported that CSF1 expressing cells also express CD68, without CD163 co-expression,

and therefore expect CSF1 expressing neoplastic cells to be derived from synovial-lining cells.

Identification of this neoplastic cell could attribute in investigations of new treatment modalities.

Dynamic contrast-enhanced MR imaging and histopathology research revealed high vascularization

in both localized- and diffuse-TGCT, showing marked enhancement on T1-weighted images with

a delayed wash-out60, 61. Angiogenesis is induced by CSF1 through vascular endothelial growth

factor (VEGF)62. Formation of blood vessels is fundamental for tumour development. A possible

therapeutic target would be to control this increased vascularity by inhibiting VEGF, for example

with Bevacizumab (Avastin)63.

2. Individually tailored treatment

It is unclear whether curation of diffuse-TGCT is possible at present, since residual tumour cells

(micro- R1 or macroscopically R2) remain after surgical resection, optimal targeted therapy is

under investigation and treatment with other therapies is inconclusive. A common question

arises: is wait and see or conservative treatment justified in the locally aggressive diffuse-TGCT?

Forthcoming research should provide answers on degree of joint destruction and (impaired)

health-related quality of life in a wait and see or conservative treatment course.

Currently, data on tumour progression after quitting targeted therapy treatment is lacking. Future

investigations should focus hereon. Also, several experimental studies with targeted therapy can

be thought of, for example investigation of intermittent use (drug holidays), the possibility of intra-

articular injection and the option of isolated limb perfusion with CSF1 blockers/inhibitors.

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Figure 2 (right page) Proposed treatment algorithm for diffuse-TGCT of large joints to be

discussed in a multidisciplinary soft tissue tumours team. Treatment proposal should balance

between disease severity and potential treatment morbidity and should be individually

tailored for each patient. Wait and see and conservative treatment are considered similar,

but should include a (2-)yearly MR imaging for follow-up to evaluate possible progressive

disease (T1- and T2-weighted fast spin echo, possibly other fluid sensitive sequences, and

preferably a scan after administration of contrast). Excision for functional improvement and

joint preservation should be proposed in symptomatic patients. An open synovectomy could

be preferred above an arthroscopic synovectomy in extra-articular disease (chapter 7), to

reduce the risk of recurrence. External beam radiation therapy can only be advised in recurrent

or severe diffuse cases and might be succeeded by targeted therapy in the near future. If

arthroplasty is anticipated, radiotherapy should not be considered lightly. As the preferred

dosage of radiotherapy is unknown, a moderate dose is recommended. Since targeted

therapy trials are ongoing, no specific targeted therapy is advised. The timing and duration

of (neo)adjuvant targeted therapy around surgery should be subject of future research.

Figure 1 Proposed treatment algorithm for localized-TGCT of large joints. Balance between disease severity

and potential treatment morbidity should be individually tailored for each patient. Wait and see and

conservative treatment are considered similar. Open resection could be preferred above an arthroscopic

resection to potentially reduce the risk of recurrence, but arthroscopic resection should not be excluded as a

potentially curative surgical technique in selected cases.

no symptoms

wait and seeTGCT severity:

severe localizedTGCT severity:mild localized

arthroscopic resection 1 staged open resection

localized-TGCT

debilitating symptoms/progressive disease


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Future treatment studies should combine current knowledge into new studies to improve

treatment modalities. Recurrent disease, (short- and long-term) complications, health-related

quality of life and joint function should be evaluated as outcome. Patients could be stratified by the

TGCT severity classification (chapter 4), that may be improved by using biological differentiation

using next generation sequencing or new MR imaging techniques. In a prospective cohort study,

several different treatment groups could be evaluated and compared:

Wait and see/conservative treatment in case of mild symptoms

Surgical treatment (open versus arthroscopic resection, one versus two-staged

synovectomy)

Neoadjuvant targeted therapy + surgical treatment

Surgical treatment + adjuvant targeted therapy

Neoadjuvant external beam radiation + surgical treatment

Surgical treatment + adjuvant external beam radiation

The intervention at group level could be implemented in stages, by use of the stepped wedge

cluster design46. Best modality to monitor response of tumour activity is yet to be established.

There might also be a role for dynamic contrast-enhanced MR imaging or fluorodeoxyglucose-

positron emission tomography (FDG-PET), as TGCT shows high FDG update64.

Evaluation of different treatment modalities, patient characteristics, disease severity and biological

behaviour could result in a prediction model. This prediction model should predict individual risk

profiles, that can then be linked to recommended treatment strategies and should take patient

characteristics, affected joint, volume of disease, disease extent, performed treatment(s) and

possibly histopathologic or genetic features into account.

3. Centralized treatment in a multidisciplinary team

The current trend in rare diseases is centralization of treatment that necessitates (highly) specialized

expertise. Diffuse-TGCT treatment should sail along this trend. In addition, centralization of diffuse-

TGCT treatment could be realized by creating more public awareness and easy available reliable

information.


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4. Patient-centred outcome measures

For future self-reported outcome evaluations in TGCT, the CAT method by use of the PROMIS item

bank could be used. Preferably in the form of an easy accessible application on a mobile device. A

new feature could be to not only link the application to the electronic patient dossier, but to also

provide feedback to each individual patient personally, on how they are performing in the field of

physical, mental and social health compared with themselves at specified time periods previously.

As TGCT is known with recurrent disease developing years after initial surgical treatment, patients

are more likely to continue completing questionnaires if they are short and simple.

302

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25. Mollon B, Griffin AM, Ferguson PC, Wunder JS, Theodoropoulos J. Combined arthroscopic and open synovectomy for

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26. Chin KR, Brick GW. Extraarticular pigmented villonodular synovitis: a cause for failed knee arthroscopy. Clin Orthop Relat

Res. 2002(404):330-8.

27. Flandry FC, Hughston JC, Jacobson KE, Barrack RL, McCann SB, Kurtz DM. Surgical treatment of diffuse pigmented

villonodular synovitis of the knee. Clin Orthop Relat Res. 1994(300):183-92.

28. Sharma V, Cheng EY. Outcomes after excision of pigmented villonodular synovitis of the knee. Clin Orthop Relat Res.

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diffuse PVNS of the knee improve recurrence rates? Clin Orthop Relat Res. 2013;471(3):883-90.


orthopaedica. 2016;87(5):497-503.

32. Hamlin BR, Duffy GP, Trousdale RT, Morrey BF. Total knee arthroplasty in patients who have pigmented villonodular

synovitis. J Bone Joint Surg Am. 1998;80(1):76-82.

33. Heyd R, Seegenschmiedt MH, Micke O. The role of external beam radiation therapy in the adjuvant treatment of

pigmented villonodular synovitis. Zeitschrift fur Orthopadie und Unfallchirurgie. 2011;149(6):677-82.



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38. Mohler DG, Kessler BD. Open synovectomy with cryosurgical adjuvant for treatment of diffuse pigmented villonodular

synovitis of the knee. Bulletin. 2000;59(2):99-105.

39. Bickels J, Isaakov J, Kollender Y, Meller I. Unacceptable complications following intra-articular injection of yttrium 90 in

the ankle joint for diffuse pigmented villonodular synovitis. J Bone Joint Surg Am. 2008;90(2):326-8.





conference 2018.







44. Sistla R, J VSV, Afroz T. Malignant Pigmented Villonodular Synovitis-A Rare Entity. Journal of orthopaedic case reports.

2014;4(4):9-11.

45. Li CF, Wang JW, Huang WW, Hou CC, Chou SC, Eng HL, et al. Malignant diffuse-type tenosynovial giant cell tumors:

a series of 7 cases comparing with 24 benign lesions with review of the literature. The American journal of surgical

pathology. 2008;32(4):587-99.

46. Dekkers OM. The stepped wedge design. Nederlands tijdschrift voor geneeskunde. 2012;156(9):A4069.


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51. Hufeland M, Gesslein M, Perka C, Schroder JH. Long-term outcome of pigmented villonodular synovitis of the hip after

joint preserving therapy. Arch Orthop Trauma Surg. 2017.

52. Gonzalez Della Valle A, Piccaluga F, Potter HG, Salvati EA, Pusso R. Pigmented villonodular synovitis of the hip: 2- to 23-

year followup study. Clin Orthop Relat Res. 2001(388):187-99.

53. Ogura K, Yasunaga H, Horiguchi H, Ohe K, Shinoda Y, Tanaka S, et al. Impact of hospital volume on postoperative

complications and in-hospital mortality after musculoskeletal tumor surgery: analysis of a national administrative

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56. Hung M, Stuart AR, Higgins TF, Saltzman CL, Kubiak EN. Computerized Adaptive Testing Using the PROMIS Physical

Function Item Bank Reduces Test Burden With Less Ceiling Effects Compared With the Short Musculoskeletal Function

Assessment in Orthopaedic Trauma Patients. Journal of orthopaedic trauma. 2014;28(8):439-43.

57. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. Journal of the

American Geriatrics Society. 1991;39(2):142-8.

58. Demers C, McKelvie RS, Negassa A, Yusuf S, Investigators RPS. Reliability, validity, and responsiveness of the six-minute

walk test in patients with heart failure. American heart journal. 2001;142(4):698-703.

59. Burton T, Ye X, Parker E, Bancroft T, Healey JH. Burden of Illness in Patients With Tenosynovial Giant Cell Tumors. ISPOR

(International Society for Pharmacoeconomics and Outcomes Research) 22nd Annual International Meeting; Boston,

MA, USA2017.

60. Dale K, Smith HJ, Paus AC, Refsum SB. Dynamic MR-imaging in the diagnosis of pigmented villonodular synovitis of the

knee. Scandinavian journal of rheumatology. 2000;29(5):336-9.




62. Curry JM, Eubank TD, Roberts RD, Wang Y, Pore N, Maity A, et al. M-CSF signals through the MAPK/ERK pathway via Sp1

to induce VEGF production and induces angiogenesis in vivo. PloS one. 2008;3(10):e3405.

63. Nissen MJ, Boucher A, Brulhart L, Menetrey J, Gabay C. Efficacy of intra-articular bevacizumab for relapsing diffuse-type

giant cell tumour. Ann Rheum Dis. 2014;73(5):947-8.

64. Amber IB, Clark BJ, Greene GS. Pigmented villonodular synovitis: dedicated PET imaging findings. BMJ case reports.

2013;2013.

sam

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(nederlandse samenvatting)

308

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nederlandse samenvatting

Tenosynoviale reusceltumoren (tenosynovial giant cell tumours, TGCT) zijn zeldzame goedaardige

tumoren. Deze aandoening werd voorheen pigmented villonodular synovitis (PVNS) genoemd.

De tumoren ontstaan vanuit het synoviale membraan van een gewricht – het membraan

dat de gewrichtsvloeistof aanmaakt, vanuit de peesschede of de slijmbeurs. Een TGCT kan

gewrichtsklachten geven als pijn, zwelling, stijfheid of bewegingsbeperking in verschillende mate

van ernst. Hierdoor kan de tumor een hoge morbiditeit veroorzaken in een relatief jonge, werkende

populatie. Op grond van klinische en radiologische kenmerken worden twee typen onderscheiden:

het gelokaliseerde type dat zich uit als een goed afgrensbare nodus, en het diffuse type dat lokaal

invasief is. TGCT kan behandeld worden met een operatie, een medicijn in onderzoeksverband en

eventueel aanvullend radiotherapie. Het is nog niet bekend welke behandeling het meest effectief

is. Het vaststellen van de meest geschikte behandeling is uitdagend doordat de tumor zo zeldzaam

is, patiënten erg van elkaar verschillen en elke behandeling andere nadelen (bijwerkingen,

recidieven, complicaties) kent.

Het doel van dit proefschrift was de kennis te verbeteren van de pathofysiologie en het biologisch

gedrag van TGCT, van het diagnostisch proces bij deze aandoening en van de kwaliteit van leven

bij TGCT-patiënten, om betere behandelmethoden te vinden. Door bewustzijn te creëren en

publiciteit te genereren, wordt bijgedragen aan de verbetering van de medische behandeling

van TGCT. In dit proefschrift worden verscheidene kennishiaten gedicht op het gebied van de

incidentie, histopathologische en hormonale karakteristieken, stratificatie van ziekte-ernst en

ziektelast bij kinderen. Daarnaast zijn de langetermijneffecten van systemische doelgerichte

therapie en de kwaliteit van leven na chirurgische behandeling onderzocht. Tenslotte wordt in

dit proefschrift de grootst bekende, wereldwijde studie gepresenteerd met individuele data van

patiënten met gelokaliseerde of diffuse TGCT.

Actuele incidentieberekeningen zijn noodzakelijk voor het diagnostisch proces. In hoofdstuk

2 is het wereldwijde incidentiecijfer berekend voor TGCT in vingers en/of tenen, gelokaliseerde

TGCT van de grote gewrichten, en voor diffuse TGCT. De tot nu toe gehanteerde TGCT-incidentie,

gebaseerd op een provinciale Amerikaanse studie uit 1980, is 9,2 voor het gelokaliseerde type

(inclusief vingers en tenen), en 1,8 per miljoen persoonsjaren voor het diffuse type (Myers 1980).

Summary in Dutch

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Door middel van het Pathologisch Anatomisch Landelijk Geautomatiseerd Archief (PALGA)

werden alle mogelijke TGCT-patiënten in Nederland geïdentificeerd, die in een periode van vijf

jaar waren gediagnosticeerd. De diagnose werd geverifieerd op basis van de klinische data in de

lokale ziekenhuizen. De Nederlandse incidentiecijfers zijn op basis van leeftijdsopbouw omgezet

naar wereldwijde incidentiecijfers. De hiermee berekende incidentie is voor TGCT van vingers en

tenen 29, voor het gelokaliseerde type van grote gewrichten 10, en voor het diffuse type 4 per

miljoen persoonsjaren. In alle drie de groepen waren vrouwen oververtegenwoordigd en was de

incidentie het hoogst in de leeftijdscategorie 40 tot 59 jaar. De knie was het vaakst aangedaan: bij

65% van de patiënten met gelokaliseerd type TGCT en bij 49% van de patiënten met diffuus type.

Het aantal heroperaties vanwege een lokaal recidief was 9% bij gelokaliseerde en 23% bij diffuse

TGCT. Vergeleken met de oorspronkelijke incidentiestudie uit Amerika, toont deze studie een 5 keer

verhoogde incidentie voor gelokaliseerde type (vingers, tenen en grote gewrichten gecombineerd)

en een 2,6 keer zo hoge incidentie voor diffuus type TGCT. Deze hogere incidentie zou verklaard

kunnen worden door onze landelijke dekking en vanwege groeiende bekendheid met de ziekte.

Het onderzoek beschreven in hoofdstuk 3 is gericht op de tegenstrijdigheid dat gelokaliseerd

en diffuus type TGCT klinisch en radiologisch verschillend zijn, maar histopathologisch niet

te onderscheiden zouden zijn. De belangrijkste stimulans voor tumorformatie in TGCT is

een overvloedige expressie van de Colony Stimulating Factor 1 (CSF1), veroorzaakt door een

genetische translocatie. Deze studie onderzocht of er een correlatie bestond tussen de expressie

en genetische herstructurering van CSF-1, en het biologisch gedrag en klinische uitkomst van

beide TGCT-subtypes – waarbij klinische uitkomst werd gedefinieerd als lokaal recidief. Langs

een continuüm van uitersten werden patiënten geselecteerd die niet eerder behandeld waren

voor TGCT van hun knie en een follow-up van minstens 3 jaar hadden. Negen patiënten met

gelokaliseerde (2 recidieven), 15 met diffuse TGCT (9 recidieven) en 4 patiënten met synovitis (als

controle) werden geïncludeerd. De gemiddelde leeftijd was 43 (spreiding 6-71) jaar en 56% was

vrouw. De combinatie van de technieken CSF1-split apart-FISH (fluorescence in situ hybridization)

na mRNA-in situ hybridization bleek een diagnostisch hulpmiddel. Hiermee werd in 76% van

de tumoren genetische herstructurering van CSF-1 gedetecteerd. Concluderend, er werd geen

duidelijk verband gevonden tussen CSF1-expressie en CSF1-herstructurering met biologisch

gedrag en klinische uitkomst.

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Binnen het gelokaliseerde en diffuse type TGCT bestaat een grote verscheidenheid in ziekte-ernst.

Daarom is in hoofdstuk 4 een classificatie ontwikkeld gebaseerd op ziekte-uitgebreidheid, om

te kunnen stratificeren tussen verschillende ziektestadia. Als eerste hebben experts parameters

gedefinieerd om de uitgebreidheid van ziekte te beschrijven op basis van een MRI scan. Vier

parameters kwamen vaker dan 20% voor op MRI, toonden goede overeenkomst binnen en tussen

beoordelaars (kappa ≥0.66) en toonden een positieve correlatie met een lokaal recidief: 1. het

TGCT-type, 2. betrokkenheid van het gewricht, 3. betrokkenheid van spier- of pees-weefsel; en

4. betrokkenheid van ligament(en). Vervolgens werd de TGCT severity classificatie voor grote

gewrichten geconstrueerd. Op basis van hazard ratio’s van de vier genoemde parameters,

aflopend van hoog naar laag, werd een classificatie met vier onderscheidende ziektestadia

gemaakt. De recidiefvrije overleving na 4 jaar (log rank p<0.0001) was 94% voor het mild localized-

stadium, 88% voor severe localized, 59% voor moderate diffuse en 36% voor het severe diffuse-

stadium. Met deze TGCT severity classificatie wordt zowel de arts als de patiënt geïnformeerd over

ziekte-uitgebreidheid en het risico op een eerste, lokaal recidief na chirurgische behandeling.

Deze classificatie kan bijdragen aan de identificatie van geschikte patiënten voor systemische

doelgerichte therapie of voor trials met nieuwe medicijnen. Daarnaast kan het toepassen van deze

classificatie, door de data meer objectiveerbaar te maken, de uitkomsten van wetenschappelijk

onderzoek naar TGCT vergelijkbaarder maken.

Patiënten rapporteren een toename van TGCT-gerelateerde klachten tijdens zwangerschap, zowel

bij polikliniekbezoeken als op online TGCT-patiëntenfora. Onze hypothese was dat dit veroorzaakt

wordt door veranderingen in vrouwelijke geslachtshormonen. Geslachtshormonen (oestrogeen

en progesteron) stijgen tijdens de zwangerschap. Hoofdstuk 5 beschrijft het eerste onderzoek

naar de invloed van vrouwelijke geslachtshormonen op symptomen van TGCT. Vijfenzestig procent

van de onderzochte zwangeren rapporteerden middels een vragenlijst een toename van TGCT-

gerelateerde symptomen, voornamelijk zwelling van het aangedane gewricht. De invloed van

geslachtspecifieke hormonen en van de vrouwelijke vruchtbare leeftijdsfasen werden beoordeeld

door het vergelijken van de recidiefvrije overleving tussen mannen en vrouwen, en tussen pre-

en postmenopauzale vrouwen. Er werd geen verschil gevonden in recidiefvrije overleving voor

geslacht (gelokaliseerd type TGCT (p=0.206 ≤50 jaar, p=0.935 >50 jaar; diffuse type (p=0.664 ≤50

jaar, p=0.140 >50 jaar)) en ook niet tussen pre- versus postmenopauzale vrouwen (gelokaliseerde

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type (p=0.106); diffuse type (p=0.666)). Dit resultaat maakt een causale relatie tussen vrouwelijke

geslachtshormonen en lokaal recidief erg onwaarschijnlijk. Daarnaast werd de oestrogeen- en

progesteronreceptor status onderzocht in TGCT-weefsel van zowel het diffuse als gelokaliseerde

type. Deze receptoren bleken afwezig. Dus ook op histopathologisch niveau werd geen verband

gevonden tussen toename van vrouwelijke hormonen en de toename van de TGCT-gerelateerde

klachten tijdens zwangerschap.

Medische publicaties over TGCT bij kinderen zijn zeldzaam: na onze systematische review blijkt

slechts over 76 kinderen met TGCT gepubliceerd te zijn. In hoofdstuk 6 worden de klinische

kenmerken en beloop van TGCT bij kinderen vergeleken met die bij volwassenen. Daarnaast wordt

de incidentie op de kinderleeftijd berekend. De gestandaardiseerde pediatrische TGCT-incidentie

van grote gewrichten was 2,42 en 1,09 per miljoen persoonsjaren in respectievelijk gelokaliseerde

en diffuse TGCT. In vier tertiaire sarcoom-centra in Nederland zijn 57 kinderen gediagnosticeerd

en behandeld tussen 1995 en 2001. Gerapporteerde symptomen waren pijn, zwelling en beperkte

bewegingsuitslag met een mediane duur van symptomen van 12 (range 1-72) maanden. Er

was geen verschil tussen kinderen en volwassenen ten aanzien van geslacht, symptomen voor

diagnose, gelokaliseerde of diffuse type, eerste behandeling, percentage lokaal recidief, follow-

upstatus of follow-upduur. De 2.5 jaar recidiefvrije overleving na open resectie was vergelijkbaar

tussen kinderen en volwassenen: respectievelijk 85% (95%CI 67%-100%) versus 89% (95%CI 83%-

96%) bij het gelokaliseerde type (p=0.527) en respectievelijk 53% (95%CI 35%-79%) versus 56%

(95%CI 49%-64%) bij het diffuse type (p=0.691). Ondanks de lage pediatrische incidentie zou TGCT

in de differentiaaldiagnose moeten staan bij kinderen met langdurige zwelling van één gewricht.

De kans op recidief-ziekte na chirurgische behandeling van deze aandoening is vergelijkbaar voor

kinderen en volwassenen.

In hoofdstuk 7 en hoofdstuk 8 wordt de tot nu toe grootste serie patiënten beschreven met

gelokaliseerd of diffuus type TGCT. Er werden 2169 patiënten geïncludeerd (941 gelokaliseerd,

1192 diffuus en 36 onbekend type) met histologisch bewezen TGCT van grote gewrichten,

behandeld tussen 1990 en 2017 in één van de 31 deelnemende internationale sarcoomcentra.

Van de patiënten met gelokaliseerd type TGCT (hoofdstuk 7) was 62% vrouw, met een mediane

leeftijd tijdens eerste behandeling van 39 jaar, en een mediane follow-up van 37 maanden. De

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knie was aangedaan in 67% en de initiële behandeling in een tertiair centrum was open resectie

in 71% van de patiënten. In totaal kreeg 13% van de patiënten een recidief, met een recidiefvrije

overleving op 3, 5 en 10 jaar van respectievelijk 88%, 83% en 79%. De grootste risicofactor voor

een lokaal recidief was het hebben van een eerder recidief (p<0.001). In 4% van alle chirurgisch

behandelde patiënten met gelokaliseerde TGCT werd een complicatie geregistreerd. Initiële

symptomen van pijn en zwelling verbeterden na chirurgische behandeling bij respectievelijk 71%

en 85% van de patiënten. Wanneer alleen niet eerder behandelde patiënten werden geïncludeerd,

werd een positieve associatie gevonden met een lokaal recidief bij een tumor grootte ≥5 cm (versus

<5cm [HR 2.50(95%CI 1.32-4.74;p=0.005)]) en na behandeling met arthroscopie (versus open

[HR 2.18(95%CI0.98-4.84;p=0.056)]). Deze associatie bleek zowel uit univariate als multivariate

analyses. Het relatief lage complicatierisico en de goede functionele uitkomsten ondersteunen de

keuze voor een open, complete resectie bij patiënten met een gelokaliseerde TGCT en een hoog

risico op recidieven, met als doel recidiefpercentages verder te verlagen.

Van de patiënten met een diffuus type TGCT (hoofdstuk 8) was 58% vrouw, met een mediane

leeftijd van 35 jaar en een mediane follow-up van 54 maanden. Het kniegewricht was aangedaan

in 64%; en 53% van de patiënten onderging als initiële behandeling een one-staged open

synovectomie in een tertiair centrum. In totaal kreeg 45% van de patiënten een lokaal recidief,

met een recidiefvrije overleving op 3, 5 en 10 jaar van respectievelijk 62%, 55% en 40%. Het

eerder hebben gehad van een recidief bleek de grootste risicofactor voor recidief van de ziekte

(HR 3.5 95%CI 2.8-4.4, p<0.001), met een 5 jaar recidiefvrije overleving van 64% in niet eerder

behandelde patiënten, vergeleken met 25% bij patiënten die elders behandeld waren en met een

recidief naar een tertiair centrum werden verwezen. 12% van de patiënten had een complicatie

als gevolg van de chirurgische behandeling. Initiële symptomen van pijn en zwelling verbeterden

na operatie bij respectievelijk 59% en 72% van de patiënten. In een subgroepanalyse van niet

eerder behandelde patiënten met TGCT in de knie, behandeld in een tertiair centrum, werd geen

verband gevonden tussen het optreden van een lokaal recidief en de volgende factoren: geslacht,

leeftijd (jonger dan 35 jaar of 35 en ouder) bot-betrokkenheid (wel of niet), chirurgische techniek

(open of arthroscopisch) en tumor grootte (kleiner dan 5cm of 5cm en groter). Onze conclusie

is dat een op zichzelf staande chirurgische behandeling niet langer de gouden standaard moet

zijn, gezien het relatief hoge complicatierisico en het zeer hoge recidiefrisico, zeker in dit tijdperk

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van multimodale therapieën. De onmogelijkheid van het uitvoeren van een radicale resectie van

diffuse TGCT, verklaart waarschijnlijk het onacceptabel hoge recidief percentage na zowel open als

arthroscopische resectie, zelfs in gespecialiseerde centra.

Hoofdstuk 9 beschrijft de lange termijneffecten van het gebruik van imatinib mesylaat, een niet-

selectieve CSF1-remmer, bij patiënten met diffuus type TGCT. In totaal 62 patiënten uit 12 centra

in Europa, Australië en de Verenigde Staten van Amerika gebruikten imatinib als behandeling. In

deze groep waren 39 patiënten vrouw (63%), met een mediane leeftijd van 45 jaar ten tijde van de

start van de behandeling en een mediane duur vanaf diagnose tot start van de behandeling van

3,5 jaar. De mediane follow-up vanaf start van de behandeling was 52 maanden. Vier patiënten

met metastasen van TGCT werden geëxcludeerd uit de analyses wegens ernstige ziekteprogressie,

ondanks behandeling met imatinib. Van de overgebleven 58 patiënten bereikten 17 gehele of

gedeeltelijke respons (29%). De progressievrije overleving van de gehele groep na 1 en 5 jaar

waren respectievelijk 71% en 48%. 38 patiënten stopten met gebruik van imatinib na 7 maanden

(66%). Gerapporteerde bijwerkingen in 45 (78%) patiënten waren voornamelijk graad 1-2 (89%)

(zoals oedeem (48%) en moeheid (50%)). Vijf patiënten ervaarden graad 3-4 toxiciteit, inclusief

neutropenie, acute hepatitis, gezichtsoedeem, huidtoxiciteit en moeheid.

Deze studie bevestigt de werkzaamheid van een tyrosinekinaseremmer zoals imatinib in

TGCT. Zelfs na staking van de behandeling werd effect gezien, echter met hoge percentages

behandelonderbrekingen en additionele behandelingen (zoals operaties). Deze resultaten geven

richting aan het effect van imatinib, met als beperking het retrospectieve studie karakter, het

ontbreken van een controlegroep en het ontbreken van patiëntgerapporteerde uitkomstmaten.

Hoofdstuk 10 beschrijft een prospectieve cohortstudie naar gewrichtsfunctie en

gezondheidgerelateerde kwaliteit van leven-uitkomsten na chirurgische behandeling, om de

patiëntgerapporteerde uitkomstmaten te evalueren. In totaal 206 opeenvolgende patiënten

met gelokaliseerd (N=108) en diffuus type (N=98) TGCT van grote gewrichten, behandeld met

arthroscopische of open synovectomie in het Leids Universitair Medisch Centrum of Radboud

Universitair Medisch Centrum, werden geïncludeerd. Patiënten rapporteerden middels het

Short Form 36 (SF-36), de Visual Analogue Scale (VAS) en de Western Ontario and McMaster

Universities Osteoarthritis Index (WOMAC). Bij zowel gelokaliseerde als diffuse TGCT scoorden

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de patiënten vooral op de fysieke component van de SF-36-subschalen significant en klinisch

relevant slechter pre-operatief en direct postoperatief vergeleken met de algemene bevolking.

Zes maanden na chirurgische behandeling verbeterden de SF-36 scores naar de gemiddelden

van de algemene populatie; deze bleven de volgende jaren tamelijk stabiel. Mediane pijnscores,

gemeten middels de VAS, vertoonden geen klinisch relevant verschil pre- of postoperatief, in geen

van beide subtypes. Pijnbeleving verschilde enorm tussen patiënten en in de tijd. Gemiddelde

functiescores (WOMAC) vertoonden in beide subtypes geen klinisch relevant verschil (effect size

< MCID 20) pre- versus postoperatief. Echter, bij diffuse TGCT-patiënten toonden pijnscores en

fysieke functiescores uit de WOMAC een trend richting verbetering pre- versus postoperatieve

scores. Op alle drie de onderzochte schalen rapporteerden patiënten een significant betere

gezondheidgerelateerde kwaliteit van leven na chirurgie voor hun TGCT, en een trend richting

verbetering van gewrichtsfunctie.

In de grootst bekende TGCT-patiënten groep werd in hoofdstuk 11 de impact van TGCT op het

dagelijks leven onderzocht. De volgende aspecten werden geëvalueerd: fysieke functie, dagelijkse

activiteiten, sociale participatie (werk, sport en hobby’s) en gezondheidgerelateerde kwaliteit

van leven. Een tweede doel was het definiëren van risicofactoren voor verslechterde uitkomsten

bij TGCT, door middel van vier gevalideerde vragenlijsten: VAS worst pain and stiffness; Patient

Reported Outcomes Measurement Information System for Physical Function (PROMIS-PF); SF-12

en EuroQoL (EQ-5D-5L). Gedurende zes maanden werden TGCT-patiënten uitgenodigd om de

online vragenlijsten in te vullen. Patiënten werden verzocht om histologisch of radiologisch bewijs

van TGCT te delen om ziekteaanwezigheid en TGCT-subtype te bevestigen. In totaal werden 337

vragenlijsten volledig ingevuld (32% met ziektebevestiging), door patiënten afkomstig uit 30

landen. De mediane leeftijd tijdens de diagnose was 33 (IQR 25-42) jaar, en de meerderheid was

vrouw (80%) en had een tumor van het diffuse type (70%) in een van de onderste ledematen: knie

(71%) en heup (10%). Het recidiefpercentage was 36% bij gelokaliseerde en 70% bij diffuse TGCT,

van in totaal 299 patiënten met TGCT in een onderste extremiteit. Ruim 1 op de 10 patiënten was

door de TGCT niet in staat om zijn of haar werk (volledig) uit te voeren (gelokaliseerde 13%, diffuse

type 11%). Meer dan de helft van de patiënten was niet in staat om sportactiviteiten te beoefenen

(gelokaliseerde type 58%; diffuse type 64%). In beide subtypes verminderden pijn en zwelling na

een chirurgische behandeling, maar stijfheid en bewegingsbeperking namen toe. Littekenweefsel,

Summary in Dutch

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15

kraakbeenslijtage en verklevingen, veroorzaakt door (meerdere) chirurgische behandelingen,

kunnen de toegenomen stijfheid en bewegingsbeperking verklaren. Vergeleken met de algemene

Amerikaanse bevolking toonden alle patiënten een klinisch relevant lagere PROMIS-PF-scores,

fysieke en mentale scores op de SF-12 en EQ-5D-5L-utiliteitscores. Wanneer het gelokaliseerde

en het diffuse type met elkaar vergeleken worden, scoorden patiënten met het diffuse type bijna

0,5 standaarddeviatie lager op de PROMIS-PF (p<0,001), en 5% lager op de EQ-5D-5L (p=0,03).

Bij patiënten met het gelokaliseerde type had de aanwezigheid van een recidief en 2 of meer

operaties een negatieve invloed op de pijn- en stijfheidscores op de VAS, fysieke scores op SF-12

en EQ-5D-5L-scores (p<0,05). In diffuse-type resulteerde recidief ziekte in lagere VAS-pijn/stijfheid,

PROMIS-PF, SF12 mentaal en EQ-5D-5L scores (p<0,05). In beide types scoorden patiënten met

behandeling korter dan 1 jaar geleden significant lager op de fysieke component van de SF-12.

Deze studie toont aan dat TGCT een grote impact heeft op het dagelijks leven in een relatief

jonge werkende patiëntenpopulatie. Artsen en andere betrokken zorgverleners, bijvoorbeeld

fysiotherapeuten, dienen zich ervan bewust te zijn dat TGCT-patiënten frequent een verminderde

kwaliteit van leven en beperkingen in hun fysiek functioneren ervaren en dat ze gehinderd blijven

in dagelijkse activiteiten zoals werk en sportactiviteiten, zelfs na behandeling(en).

Hoofdstuk 12 beschrijft een extreme, definitieve behandelingsmaatregel bij TGCT: een

bovenbeenamputatie. Bij diffuse TGCT is er zeer vaak sprake van recidieven (tot wel 92%

beschreven), die heroperaties en aanvullende behandelingen noodzakelijk maken. Als alle

behandelingen falen of ernstige complicaties optreden, kan amputatie onvermijdelijk zijn. Dit

hoofdstuk beschrijft vier ziektegeschiedenissen waarin een amputatie van het bovenbeen het

laatste redmiddel bleek.

Concluderend, TGCT is een chronische ziekte met een grote impact op het dagelijks leven. Voor

artsen is het uitdagend om de optimale gepersonaliseerde behandeling te bewerkstelligen, omdat

TGCT patiënten erg van elkaar verschillen, trials met doelgerichte therapie nog gaande zijn en er

geen gestandaardiseerd behandel algoritme bestaat. Als fundament en om verder te ontwikkelen

wordt een behandel algoritme voorgesteld voor TGCT van alle grote gewrichten in hoofdstuk

14. Dit algoritme is gebaseerd op onze ervaring, de literatuur en de TGCT severity classificatie op

MRI scans (hoofdstuk 4). Naast de fysieke en financiële last voor de patiënt zorgt TGCT ook voor

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stijgende medische kosten na diagnose. Huidige ontwikkelingen zijn veelbelovend: groeiend

bewustzijn, centralisatie van zorg, verscheidene doelgerichte therapie trials, evaluatie van

gepersonaliseerde follow-up vragenlijsten en lopende prospectieve internationale samenwerking

studies. Deze initiatieven moeten uitgebreid worden om nieuwe inzichten te krijgen in TGCT.

De discussie, klinische implicaties en toekomstperspectieven over het onderwerp van dit

proefschrift worden besproken in hoofdstuk 14.

Summary in Dutch

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15

aPP

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chap

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Chapter sixteen

list of publications

Appendices

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16

scientific articles

Outcome of surgical treatment for patients with diffuse-type Tenosynovial Giant Cell Tumours

M.J.L. Mastboom, E. Palmerini, F.G.M. Verspoor, A.J. Rueten-Budde, S. Stacchiotti, E. Staals, G.

Schaap, P.C. Jutte, W. Aston, H. Gelderblom, A. Leithner, D. Dammerer, A. Takeuchi, Q. Thio, X. Niu,

J.S. Wunder, TGCT study group & M.A.J. van de Sande

Submitted

Surgical treatment of localized-type Tenosynovial Giant Cell tumours of large joints

M.J.L. Mastboom, E. Staals, F.G.M. Verspoor, A.J. Rueten-Budde, S. Stacchiotti, E. Palmerini, G.

Schaap, P.C. Jutte, W. Aston, A. Leithner, D. Dammerer, A. Takeuchi, Q. Thio, X. Niu, J.S. Wunder, TGCT

study group & M.A.J. van de Sande

Submitted

Can increased symptoms of Tenosynovial Giant Cell Tumours during pregnancy be explained by a

change in female sex hormones?

M.J.L. Mastboom, F.G.M. Verspoor, R. Planje, H.W.B. Schreuder, M.A.J. van de Sande

Submitted

Long-term efficacy of imatinib mesylate in patients with advanced Tenosynovial Giant Cell Tumour

M.J.L. Mastboom*, F.G.M. Verspoor*, G. Hannink, R.G. Maki, A. Wagner, E. Bompas, J. Desai, A.

Italiano, B.M. Seddon, W.T.A. van der Graaf, J.Y. Blay, M. Brahmi, L. Eberst, S. Stacchiotti, O. Mir, M.A.J.

van de Sande, H. Gelderblom, P.A. Cassier (*Shared first authorship)

Submitted

Outcome after 52 Salto Ankle prostheses implanted by a single surgeon

F.W.M. Faber, M.J.L. Mastboom, S.T. van Vliet-Koppert, I.C.E. Bouman, P.M. van Kampen

Adv Orthopedics. 2018 Aug;2735634 doi: 10.1155/2018/2735634

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The effect of surgery in Tenosynovial Giant Cell Tumours as measured by patient reported

outcomes on quality of life and joint function

M.J.L. Mastboom*, F.G.M. Verspoor*, G. Hannink, W.T.A. van der Graaf, M.A.J. van de Sande, H.W.B.

Schreuder (*Shared first authorship)

Accepted in Bone Joint J

Does CSF1 over-expression or rearrangement influence biological behaviour in tenosynovial giant

cell tumours of the knee?

M.J.L. Mastboom, D.M. Hoek, J.V.M.G. Bovée, M.A.J. van de Sande, K. Szuhai

Histopathology. 2018 Aug; doi: 10.1111/his.13744


M.J.L. Mastboom*, F.G.M. Verspoor*, D.F. Hanff, M.G.J. Gademan, P.D.S. Dijkstra, H.W.B. Schreuder,

J.L. Bloem, R.J.P. van der Wal, M.A.J. van de Sande (*Shared first authorship)

Surg Oncol. 2018 Sept;27(3):544-550. doi.org/10.1016/j.suronc.2018.07.002

Incidence and Demographics of Giant Cell Tumor of Bone in The Netherlands: First Nationwide

Pathology Registry Study

A.J. Verschoor, J.V.M.G. Bovée, M.J.L. Mastboom, P.D.S. Dijkstra, M.A.J. van de Sande, H. Gelderblom

Acta Orthop. 2018 Jul 10:1-5. doi: 10.1080/17453674.2018.1490987

Tenosynovial Giant Cell Tumors in Children: A Similar Entity Compared With Adults

M.J.L. Mastboom, F.G.M. Verspoor, D. Uittenbogaard, G.R. Schaap, P.C. Jutte, H.W.B. Schreuder,

M.A.J. van de Sande


The Patient Perspective on the Impact of Tenosynovial Giant Cell Tumors on Daily Living:

Crowdsourcing Study on Physical Function and Quality of Life.

M.J.L. Mastboom, R. Planje, M.A.J. van de Sande

Interact J Med Res. 2018 Feb 23. doi: 10.2196/ijmr.9325

Appendices

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Treatments of Tenosynovial Giant Cell Tumors of the Temperomandibular joint -Report of three

cases and a review of literature

F.G.M. Verspoor, M.J.L. Mastboom, W.L.J. Weijs, A.C. Koetsveld, H.W.B. Schreuder, U. Flucke

Int J of Oral Maxillofac Surg. 2018 april doi.org/10.1016/j.ijom.2018.04.001

Higher incidence rates than previously known in tenosynovial giant cell tumors.

Mastboom M.J.L., Verspoor, F.G.M., Verschoor A.J., Uittenbogaard D., Nemeth B., Mastboom W.J.B.,

Bovée J.V.M.G., Dijkstra P.D.S., Schreuder H.W.B., Gelderblom H., Sande van de M.A.J., TGCT study group.

Acta Orthop. 2017 Aug 8:1-8. doi: 10.1080/17453674.2017.1361126

Limb Amputation after Multiple Treatments of Tenosynovial Giant Cell Tumour: Series of 4 Dutch Cases.

Mastboom M.J.L., Verspoor F.G.M., Gelderblom H., van de Sande M.A.J.

Case Rep Orthop 2017 Jun 28. doi: 10.1155/2017/7402570

Functional outcome and quality of life after the surgical treatment for diffuse-type giant-cell

tumour around the knee: a retrospective analysis of 30 patients.

van der Heijden L., Mastboom M.J.L., Dijkstra P.D.S., van de Sande M.A.J.

Bone Joint J 2014 Aug;96-B(8):1111-8. doi: 10.1302/0301-620X.96B8.33608

oral presentations

Tenosynovial Giant Cell Tumours: surgery or targeted therapy?

EMSOS 2018 Amsterdam, The Netherlands

Riskfactors in Tenosynovial Giant Cell Tumours

EMSOS 2018 Amsterdam, The Netherlands; BOOS 2018 Edinburgh, Scotland; MSTS 2018 NYC, USA;

CTOS 2018 Rome, Italy

Role of CSF1 in Tenosynovial Giant Cell Tumours

EMSOS 2018 Amsterdam, The Netherlands; BOOS 2018 Edinburgh, Schotland

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The patient perspective on the impact of Tenosynovial Giant Cell Tumors on daily living

EMSOS 2018 Amsterdam, The Netherlands


BOOS 2018 Edinburgh, Scotland; EMSOS 2017 Budapest, Hungary; CTOS 2017 Hawaii, USA

Tenosynovial Giant Cell Tumours affecting large joints in Children

ISOLS 2017 Kanazawa, Japan; EPOS 2018 Oslo, Norway

A nationwide study on Tenosynovial Giant Cell Tumours in the Netherlands

ISOLS 2017 Kanazawa, Japan; EMSOS 2017 Budapest, Hungary; NOV 2017 Den Bosch, The Netherlands

Preliminary results on the international multicenter retrospective Tenosynovial Giant Cell Tumour Study

EMSOS 2016 La Baule, France; MSTS 2016 Detroit, USA; CTOS 2016 Lisbon, Portugal

Tenosynovial Giant Cell Tumours Observational Platform Project (TOPP)

ESMO 2016 Copenhagen, Denmark

Heeft pre-operatief een 3T-MRI nut bij chronische polsklachten?

NOV 2015 Den Bosch, The Netherlands; scientific meeting LUMC, Leiden, The Netherlands

Functional outcome and quality of life after the surgical treatment for diffuse-type giant-cell tumours

ISOLS 2013, Bologna, Italy; ISCOMS 2013, Groningen, The Netherlands

Poster presentations

Prospective multicenter study in diffuse-type Tenosynovial Giant Cell Tumours

EMSOS 2018 Amsterdam, The Netherlands; ASCO 2018 Chicago, USA


MSTS 2018 NYS, USA

CSF1 over-expression and CSF1 split do not predict clinical outcome in Tenosynovial giant cell tumours

CTOS 2017 Hawaii, USA; MSTS 2018 NYC, USA; CTOS 2018 Rome, Italy

Appendices

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The effect of Tenosynovial Giant Cell Tumours on daily living; an online cross-sectional analysis of

functionality and quality of life in 337 patients

CTOS 2017 Hawaii, USA

First results of the international multicenter retrospective Tenosynovial Giant Cell Tumour Study

ISOLS 2017 Kanazawa, Japan

Consider Tenosynovial Giant Cell Tumours in chronic mono-arthritis in children

EMSOS 2017 Budapest, Hungary

Limb amputation as a result of Tenosynovial Giant Cell Tumour

EMSOS 2016 La Baule, France

What is the use of 3T-MRI in chronic wrist complaints?

Haga scientific day and nurse evening 2015, The Hague + SEOHS 2015, Leiden, The Netherlands

Functional results and quality of life after open synovectomy for giant cell tumors of synovium in

the knee

CTOS 2013 New York City, USA + EMSOS 2013 Gothenburg, Sweden

awards and honors

Best Oral Talk award. BOOS Edinburgh, Schotland, 2018

Young Investigator award. CTOS Hawaii, USA, 2017

Nomination Best Paper award. ISOLS Kanazawa, Japan, 2017

Young Investigator award. MSTS Detroit, USA, 2016

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acknowledgements

Appendices

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16

Met behulp van dit proefschrift hebben we een bijdrage kunnen leveren aan het verder ontrafelen

van de mysteriën omtrent een ongelooflijk interessant ziektebeeld: tenosynoviale reusceltumoren.

Veel dank aan alle nationale en internationale TGCT-patiënten die bereid zijn geweest hun

persoonlijke ervaringen te delen, zowel op de poli, als op Facebook, als via hun artsen.

Dankzij de hulp, de adviezen en het geduld van velen, is dit proefschrift tot stand gekomen.

Hiervoor wil ik onderstaande personen heel hartelijk bedanken:

Dr. M.A.J. van de Sande, ik voel me zeer vereerd om een van jouw eerste promovenda te mogen

zijn. Jouw enthousiasme werkt zo aanstekelijk dat ik in een mum van tijd een recordaantal

projecten was gestart, in samenwerking met verschillende afdelingen en ziekenhuizen. Gelukkig

heb ik het merendeel, mede dankzij jouw volhardendheid, weten af te ronden. Jouw talent voor

multi-tasken is bewonderenswaardig. Ik heb altijd kunnen rekenen op 100% toewijding en zeer

snelle feedback. Dankzij jou heb ik het belang van (internationale) samenwerking ingezien en écht

onderzoek leren doen. Bedankt voor de sturing en het vertrouwen en alle kansen in zowel binnen-

en buitenland.

Prof. Dr. P.D.S. Dijkstra, inspirerend hoe jij kliniek en wetenschap weet te combineren en hoe de

patiënt daarin altijd centraal staat. Bedankt voor je inzet en enthousiasme, de begeleiding van mijn

wetenschappelijke carrière, de kritische noot zo nodig, het mentorschap en de deur die altijd openstaat.

Prof. Dr. H. Gelderblom, bedankt voor de introductie in de medische oncologie. Door de vrijheid

en ruimte die ik kreeg, waarbij ik altijd binnen kon lopen voor een discussie, heb ik me verder

kunnen ontplooien.

Prof. Dr. R.G.H.H. Nelissen en stafleden orthopaedie, bedankt voor alle mogelijkheden en kansen

die ik heb gekregen op de afdeling orthopaedie, welke ik altijd graag met beide handen aangreep.

Prof. Dr. H.W.B. Schreuder, zonder de intensieve samenwerking met Nijmegen was dit boek niet

half zo mooi geworden. Door onze samenwerking kwamen er veel gedegen studie-initiatieven,

werden alle data verdubbeld, kritisch geëvalueerd en uiteindelijk afgerond middels een presentatie

en publicatie. Bedankt voor deze solide basis.

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Dr. F.G.M. Verspoor, dankzij onze power-samenwerking, duidelijke afspraken, heftige discussies

en zorgvuldige werken zijn onze beider proefschriften naar een hoger niveau gebracht. Tijdens

onze (langdurige) telefoongesprekken ontstonden altijd weer nieuwe initiatieven en ideeën of

juist oplossingen voor bestaande problemen. Samen hebben wij bijgedragen aan het verder

ontrafelen van deze interessante, soms ongrijpbare ziekte. Ik ben erg trots dat we dit samen

hebben gedaan!

Alle collaborating centers, co-auteurs in binnen- en buitenland: veel dank. Door gedegen

samenwerking wordt er steeds meer bekend over deze eerder zo ongrijpbare ziekte. Breaking borders!

Dear co-authors from all over the world, thank you for your collaboration in our national and

international studies: I greatly appreciate it.

Collegae van de C3 en later C2, zonder jullie relativeringsvermogen en humor was dit traject niet

zo bruisend geweest!

Medische studenten Daniël, Rosa, Willemijn, Femke en Marijn, jullie enthousiasme en frisse blik

hebben enorm bijgedragen aan dit proefschrift.

Secretaresses van de orthopaedie, Anika, Saskia en Marisa, altijd erg fijn dat jullie snel en

adequaat regelen wat er geregeld moest worden.

Maartje en Britta, mijn keuze voor jullie als mijn paranimfen was snel gemaakt. Sinds de

middelbare school zijn we een onafscheidelijk drietal, ook al zijn we soms duizenden kilometers

van elkaar verwijderd. Ik hou niet van verrassingen, alleen van die van jullie!

Masque en QQ, vooral ProzaQQ, bedankt voor de betrokkenheid en zeer welkome afleiding.

Lieve Gerritje en Marieke: de leuksten, dat blijven we!

Appendices

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16

Marja en Romy, erg fijn om tegelijkertijd in ‘hetzelfde schuitje’ te zitten.

Lisanne, bedankt voor je niet aflatende interesse in mijn onderzoek en je inspirerende design

skills: ik ben heel trots op de omslag en lay-out van dit proefschrift. Voor ons is geen berg te hoog ;)

Hardloopbuddy’s, LUHV Currimus vooral Dave, Jan G, Jan vR, Bart en Chris, jullie geven me altijd

veel energie.

Mam, bedankt voor je geduld en dat je altijd naar mijn nog-net-niet-affe presentaties wilde

luisteren. Pap, bedankt voor je inhoudelijke discussies als ik vastgelopen was. Elvire, Bas, Daphne

en Joost, verstand op nul is het allerleukst met jullie.

Liefste Leander, mijn altijd aanwezige steun en toeverlaat, naar jou gaat de meeste dank uit.

Jouw robuuste vertrouwen in mij, geeft mij kracht en energie om hoge(re) doelen te bereiken.

Jouw relativeringsvermogen heeft sterk bijgedragen aan de afronding van dit proefschrift en het

feestelijke etentje bij iedere publicatie houden we erin. Wij samen zijn een super-team!

Alle anderen die op enigerlei wijze hebben bijgedragen aan de totstandkoming van dit proefschrift

wil ik hiervoor hartelijk danken.

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curriculum vitae

Appendices

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Monique Josephine Leonie Mastboom was born in Nijmegen on October 19th 1988 and grew up

in a family of six in Enschede, The Netherlands. In 2004-2005 she spent a year as exchange student

in Bloomfield Hills, Michigan, USA, where she played ice-hockey and ran cross-country in the varsity

team. Two years after high school graduation in the USA, she also graduated from VWO profile

nature & health at Bonhoeffer college, Enschede. In that same year she started medical school in the

LUMC, Leiden. In 2008 she founded the Leids Universitaire Hardloopvereniging (LUHV) Currimus,

with which she organized and attended multiple relay races and cross-country tournaments.

Between 2009 and 2010 joined the board of the Enige Leidse Commissie Introductie Dagen (EL CID),

to organize the introduction week for new students. While joining several medical missions in the

Amazon jungle of Peru in 2011, she assisted during large traumatic, orthopaedic and reconstructive

surgeries and her interest in the functioning of the musculoskeletal system was enlarged.

After graduating from Medical School, she started working as ANIOS Orthopaedics in the Haga

Hospital, The Hague. In 2016 her research internship on Tenosynovial Giant Cell Tumours at the

department of Orthopaedic Surgery at the LUMC, Leiden was started. During this internship she

visited 95 hospitals in The Netherlands for an incidence calculation study, collaborated with the

other three Dutch orthopaedic oncologic centres (Prof. Dr. H.W.B. Schreuder, Drs. F.G.M. Verspoor, Dr.

G.R. Schaap, Dr. P.C. Jutte), collaborated with 30 international sarcoma centres and worked together

with seven different departments in the LUMC. This research resulted in a series of translational,

clinical and multicentre studies that formed the base of this PhD-thesis (Prof. Dr. P.D.S. Dijkstra, Prof.

Dr. A.J. Gelderblom, Dr. M.A.J. van de Sande). Most studies were presented at international scientific

meetings, awarded at the annual MSTS conference in Detroit 2016 with the young investigator

award, at the bi-annual ISOLS conference in Kanazawa 2017 with a nomination for the best paper

award, at the annual CTOS conference in Hawaii 2017 with the young investigator award and at the

annual BOOS conference in Edinburgh 2018 with the best oral talk award. Monique will continue

her orthopaedic career in Regionale Opleiding Groep Orthopaedie Oost.

During her medical training and research internship she ran four marathons (New York 2013, Tokyo

2015, Valencia 2015, Amsterdam 2017) and three running climbs during the Alpe d’HuZes (2017).

Monique lives together with Leander Lignac in Amsterdam. They are expecting their first child in

February 2019.

Although it’s rare, it still needs care !

tenosynovial giant cell tumours

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